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CA 02441397 2003-09-19
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Human Secreted Proteins
Field of the Invention
The present invention relates to human secreted proteins/polypeptides, and
isolated nucleic
acid molecules encoding said proteiris/polypeptides, useful for detecting,
preventing, diagnosing,
prognosticating, treating, and/or ameliorating gastrointestinal diseases and
disorders. ' Antibodies
that bind these polypeptides are also encompassed by the present invention.
Also encompassed by
the invention are vectors, host cells, and recombinant and synthetic methods
for producing said
polynucleotides, polypeptides,, and/or antibodies. The invention further
encompasses screening
methods for identifying agonists and antagonists of polynucleotides and
polypeptides of the
invention. The present invention further encompasses methods and compositions
for inhibiting or
enhancing the production and function of the polypeptides of the present
invention.
Background of the Invention
The human digestive system is a collection of specialized organs and body
tissues that
prepare food for use by hundreds of millions of body cells. Food when eaten
cannot reach cells
because it cannot pass through the intestinal walls to the bloodstream and, if
it could would not be
in a useful chemical state. The gastrointestinal system modifies food
physically and chemically
and disposes of unusable waste. Physical and chemical modification (digestion)
depends on
exocrine and endocrine secretions and controlled movement of food through the
digestive tract.
The three fundamental processes of the digestive system are: secretion (e.g.,
delivery of
enzymes, mucus, ions and the like into the lumen, and hormones into blood),
absorption (e.g.,
transport of water,, ions and nutrients from the lumen, across the epithelium
and into blood), and
motility (e.g., contractions of smooth muscle in the wall of the tube that
crush, mix and propel its
contents). Control of digestive function is achieved through a combination of
electrical and
hormonal messages which originate either within the digestive system's own
nervous and
endocrine systems, as well as from the central nervous system and from
endocrine organs such as
the adrenal gland.
The digestive system is composed of the digestive or alimentary tube and
accessory
digestive organs, which include the Mouth (e.g., tongue, taste buds, soft
palate pharynx, salivary
glands, teeth), Esophagus, Stomach, Liver, Gallbladder, Pancreas, Small
Intestine (e.g.,
duodenum, jejunum, and ileum), and Large Intestine (e.g., caecum).
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Common digestive system disorders including infections, inflammations, ulcers
and
cancers of the digestive or alimentary tube and above listed accessory
digestive organs are
described in more detail below.
Disorders of the Mouth
The mouth comprises an area from the lips to the front of the tonsils (fauces)
at the start of
the throat. The mouth contains the gums, teeth, and the tongue, together with
salivary glands
which secrete fluids that lubricate and begin food digestion as it is chewed.
The roof of the mouth
consists of the hard palate at the front and the soft palate at the back. The
floor of the mouth
comprises the tongue (controlled by a number of muscles attached to bones in
the neck). At the
front and sides of the tongue there are a number of taste buds. These respond
to different tastes at
different places (e.g., sweet, salty, sour, and bitter). At the back of the
tongue there are some
swellings which consist of lymphoid tissue. Underneath the tongue there is a
midline attachment
(frenulum) and the opening of several of the salivary ducts. There are other
salivary glands (the
parotid glands) lying over the angle of the jaw with a duct opening to the
inside of the cheek at
about the level of the second molar tooth.
Diseases and disorders of the mouth are vary greatly in manifested symptoms,
frequencies,
severities, and causes. Accordingly, diseases and disorders of the mouth may
be caused or
initiated by viruses, bacteria, genetics (e.g. autoimmune disorders), physical
or chemical trauma,
etc. For example, diseases and disorders of the mouth include canker sores
(aphthous ulcers),
herpetic stomatitis leukoplakia, gingivostomatitis, oral cancer, oral lichen
lanus, oral thrush,
histoplasmosis, salivary gland infections, glossitis, Hand, Foot and Mouth
disease, salivary duct
stones, mumps, etc.
Disorders of the Esophagus
Disorders of the Esophagus include dysphagia (e.g., difficulty in swallowing)
and
odynophagia (e.g., difficulty in swallowing accompanied by pain). Inflammatory
disorders of the
esophagus result from a variety of causes; for example, ingestion of noxious
materials (e.g.,
corrosive esophagitis), lodgment of foreign bodies, or a complex of events
associated with reflux
of gastric contents from the stomach into the lower esophagus (e.g., peptic
esophagitis).
Disorders of the motility of the esophagus tend to be either precipitated or
aggravated at
times of nervous stress. A disorder commonly due to obesity is gastric reflux.
Persisting reflux of
gastric contents with acid and digesting enzymes leads to chemical
inflammation of the lining of
the esophagus and ultimately to (peptic) ulceration. If inadequately treated,
the process leads to
submucosal fibrosis and stricturing, and, besides the symptoms of heartburn
and regurgitation, the
patient experiences pain on eating and swallowing.
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Further disorders of the esophagus include the formation of diverticula. A
serious injury to
the esophagus is spontaneous rupture. It can occur in patients who have been
vomiting or retching
and in debilitated elderly persons with chronic lung disease. A rupture of
this type confined to the
mucosa only at the junction of the linings of the esophagus and stomach is
called a Mallory-Weiss
lesion.
Benign tumors of the esophagus originate in the submucosal tissues and
principally are
leiomyomas (tumors composed of smooth muscle tissue) or lipomas (tumors
composed of adipose,
or fat, tissues). Malignant tumors are either epidermal cancers, made up of
unorganized aggregates
of cells, or adenocarcinomas, in which there are gland-like formations.
Cancers arising from
squamous tissues are found at all levels of the organ, whereas adenocarcinomas
are more common
at the lower end where a number of glands of gastric origin are normally
present. The prognosis is
poor because diagnosis is difficult and the tumor has usually been growing for
one or two years
before symptoms are apparent.
Disorders of the stomaclz
Any disorder that affects the power of coordination of the stomach muscles is
capable of
producing symptoms ranging from those that are mildly unpleasant (e.g.,
anorexia and nausea) to
others that axe life-threatening. The intrinsic muscles of the stomach are
innervated by branches of
the vagus nerves, which travel along the esophagus from their point of
emergence in the brain
stem. Severing these nerves or altering their function by the use of
anticholinergic medication may
produce temporary or more prolonged change in the ability of the stomach to
empty itself. Gastric
retention may result from the degeneration of the nerves to the stomach that
can result from
diabetes mellitus. Obstruction due to scarring in the area of the gastric
outlet, or to tumors
encroaching on the lumen, causes the stomach to fill up with its own
secretions as well as with
partially digested food. In these circumstances, vomiting leads to dehydration
and to electrolyte
losses, which threaten life if not corrected.
Disorders of the stomach include ulcerative diseases, which involve mucosal
breakdown
either confined to the supe~cial layers of the mucosa (e.g., an erosion) or
extending through the
intrinsic layer of muscle of the mucosa into the tissues below (e.g., an
ulcer). The circumstances
that contribute to mucosal injury and ulcer formation include physical and
chemical trauma that
result from hot fluids and food, aspirin and other drugs, irritating spices,
and pickling fluids. In
addition, genetic factors are involved in the development of ulcers. The
complications of peptic
ulcers are hemorrhage, perforation, and obstruction of the outlet of the
stomach (pyloric stenosis)
by scarnng of the duodenal bulb or of the pyloric channel. A diffuse
inflammation of the stomach
lining, gastritis, is usually an acute process caused by contaminated food,
alcohol abuse, or by
bacterial- or viral-induced inflammation of the gastrointestinal tract
(gastroenteritis). ~ The other
form of gastritis is gastric atrophy, in which the thickness of the mucosa is
diminished. Diffuse
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gastric atrophy leads to partial loss of the glands and secreting cells
throughout the stomach and
may be associated with iron-deficiency anemia.
Malignant tumors of the stomach are common and are probably a result of both
genetic
and environmental factors. Gastric cancer affects men more often than women
and accounts for
about 20 percent of all deaths from cancers of the gastrointestinal tract in
the United States. Other,
malignant tumors that involve the stomach are tumors ordinarily made up of
lymphoid and
connective tissue. Benign tumors, especially leiomyomas, are common and may,
when large, cause
massive hemorrhage. Polyps of the stomach are not common except in the
presence of gastric
atrophy.
Disorders of the Duodenum and Small Intestine
Primary cancer of the duodenum is an infrequent disease, however, benign
tumors of the
duodenum, particularly polyps and carcinoids, are more frequent. Cancers of
the common bile duct
or of the pancreas are important causes of death. A common disorder of the
small intestine,
distension, is caused by lack of coordination of the inner circular and outer
longitudinal muscular
layers of the intestinal wall which usually results in an accumulation of
excess contents in the
lumen. The most common cause of disturbed motility in the small intestine is
food that contains an
unsuitable additive, organism, or component. One of the most serious problems
in small intestine
are motor disturbances which arise from an intestinal obstruction that results
from an actual
encroachment on the bowel by an adhesive band or from an internal block
produced by a tumor or
gallstone. In addition, as profound an obstruction results when a portion of
the intestine undergoes
partial necrosis, or death, from failure of its blood supply.
The extremely common disorder known as the irritable bowel syndrome is
probably due to
a disturbance of the motility of the whole intestinal tract. The symptoms vary
from watery diarrhea
to constipation and the passage of stools with difficulty. When the colon is
involved, an excess of
mucus is often observed in the stools. Occasionally the irritable bowel
syndrome may be due to an
allergy to a particular foodstuff. The syndrome may develop following an
infection such as
bacillary dysentery, after which the small intestine remains irritable for
many months.
A further disorder, malabsorption occurs when the small intestine is unable to
transport
properly broken down products of digestive materials from the lumen of the
intestine into the
lymphatics or mesenteric veins, where they are distributed to the rest of the
body. Defects in
transport occur either because the absorptive cells of the intestine lack
certain enzymes, whether
by birth defect or by acquired disease, or because they are hindered in their
work by other disease
processes that infiltrate the tissues, disturb motility, permit bacteria to
overpopulate the bowel, or
block the pathways over which transport normally proceeds. A malabsorption
disorder of unknown
cause, tropical spree, is associated with partial atrophy of the mucosa of the
small intestine.
Disorders of the small intestine also include bacterial and parasitic
infections.
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Appendicitis is an inflammation of the vermiform appendix that may be caused
by
infection or partial or total obstruction. Chronic inflammations of the small
intestine include
tuberculosis and regional enteritis (Crohn's disease). Celiac disease causes
damage to the mucosa
of the small intestine, though it is not clear whether it is caused by an
immune reaction, or an
inability to break down a toxic protein, gluten, to smaller peptide fractions.
Studies of the immune
function of those with celiac disease suggest that at least a major part of
the process is a delayed
hypersensitivity reaction and that the morphological changes are correlated
with the presence of
circulating antibodies to gluten. The mucosal reaction results in progressive
atrophy, with
dwarfing, if not complete disappearance, of the microvilli and villi that line
the intestinal tract.
Disorders of the Large Intestine
A wide variety of diseases and disorders occur in the large intestine. A
disease that is
analogous to achalasia of the esophagus is an idiopathic condition called
aganglionic megacolon,
or Hirschsprung's disease. It is characterized by the absence of ganglion
cells and normal nerve
fibres from the distal (or lower) portion of the large intestine, which
results in reduced
neuromuscular transmission and ceased peristalsis. The entire colon slowly
becomes more and
more distended and thick-walled. Abscesses in the perianal area are common
complicating features
of many diseases and disorders of the large intestine. Fungal and bacterial
infections are also
common causes of large intestine disorders.
The most common form of chronic colitis, ulcerative colitis, is idiopathic. It
varies from a
mild inflammation of the mucosa of the rectum, giving rise to excessive mucus
and some spotting
of blood in the stools, to a severe, sudden, intense illness, with destruction
of a large part of the
colonic mucosa, considerable blood loss, toxemia and, less commonly,
perforation. The most
common variety affects only the rectum and sigmoid colon and is characterized
by diarrhea and
the passage of mucus. Apart from the greater tendency for fistulas to form and
for the wall of the
intestine to thicken until the channel is obstructed, Crohn's disease is
distinguishable from
ulcerative colitis by microscopic findings. In Crohn's disease, the maximum
damage occurs
beneath the mucosa, and lymphoid conglomerations, known as granulomata, are
formed in the
submucosa. Crohn's disease attacks the perianal tissues more often than does
ulcerative colitis.
Although these two diseases are not common, they are disabling.
Tumors of the colon are usually polyps or cancers. A peculiar form of polyp is
the villous
adenoma, often a slowly growing, fernlike structure that spreads along the
surface of the colon for
some distance. Cancers compress the colonic lumen to produce obstruction, they
attach to
neighbouring structures to produce pain, and they perforate to give rise to
peritonitis. Cancers also
may metastasize to distant organs before local symptoms' appear.
Anorectal disorders related to defecation are more common in the Western world
than
elsewhere. These disorders usually take the form of fissures (cuts or cracks
in the skin or mucous
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membrane) at the junction of the anal mucous membrane with the skin between
the thighs. Anal
fistulas sometimes occur as complications of serious bowel disease, as in
tuberculosis or Crohn's
disease of the bowel, or in certain parasitic diseases. A more general
disorder is the enlargement of
veins of the rectum and anus to form external or internal hemorrhoids.
Hemorrhoids protrude, are
associated with anal itching and pain, and bleed, especially when they come in
contact with hard
stools.
Disorders of the Liver
A variety of agents, including viruses, drugs, environmental pollutants,
genetic disorders,
and systemic diseases, can affect the Liver. The resulting disorders usually
affect one of the three
functional components of the liver: the hepatocyte (liver cell) itself, the
bile secxetory
(cholangiolar) apparatus, or the blood vascular system. Most acute liver
diseases are self limited,
and liver functioning returns to normal once the causes are removed or
eliminated. In some cases,
however, the acute disease process destroys massive areas of liver tissue in a
short time, leading to
extensive death (necrosis) of hepatic cells and often to death of the patient.
Hepatitis may result
from viral infections or toxic damage from drugs or poisons. When acute
hepatitis lasts for six
months or more, a slow but progressive destruction of the surrounding Liver
cells and bile ducts
occurs, a stage called chronic active hepatitis. If hepatocellular damage is
severe enough to destroy
entire acini (clusters of lobules), they are often replaced with fibrous scar
tissue. Bile canaliculi
and hepatocytes regenerate in an irregular fashion adjacent to the scar tissue
and result in a chronic
condition called cirrhosis of the liver. Whexe inflammatory activity continues
after the onset of
cirrhosis, the disorderly regeneration of hepatocytes and cholangioles may
lead to the development
of hepatocellular or cholangiolar cancer.
Although a number of viruses affect the liver, including the cytomegalovirus
of infancy
and childhood and the Epstein-Barn virus of infectious mononucleosis, there
are three distinctive
transmissible viruses that are specifically known to cause acute damage to
liver cells: hepatitis
virus A (HAV), hepatitis virus B (HBV), and hepatitis virus non-A, non-B
(NANB). The
symptoms characteristic of the acute hepatitis caused by the HAV, HBV, and
NANB viruses are
essentially indistinguishable from one another.
Acute hepatitis also may be caused by the overconsumption of alcohol or other
poisons,
such as commercial solvents (e.g., carbon tetrachloride), acetaminophen, and
certain fungi. Such
agents are believed to cause hepatitis when the formation of their toxic
intermediate metabolites in
the liver cell (phase I reactions) is beyond the capacity of the hepatocyte to
conjugate, or join them
with another substance for detoxification (phase II reactions) and excretion.
Acute canalicular
(cholestatic) hepatitis is most commonly caused by certain drugs, such as
chlorpromazine, that
lead to idiosyncratic reactions or, at times, by hepatitis viruses. Acute
congestive liver disease
usually results from the sudden engorgement of the liver by fluids after
congestive heart failure.
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A prominent autoimmune liver disease is Wilson's disease, which is caused by
abnormal
deposits of large amounts of copper in the liver. Granulomatous hepatitis, a
condition in which
localized areas of inflammation (granulomas) appear in any portion of the
liver lobule, is a type of
inflammatory disorder associated with many systemic diseases, including
tuberculosis, sarcoidosis,
schistosomiasis, and certain drug reactions. Granulomatous hepatitis rarely
leads to serious
interference with hepatic function, although it is often chronic. The end
result of many forms of
chronic liver injury is cirrhosis, or scarring of liver tissue in reponse to
previous acinar necrosis
and irregular regeneration of liver nodules and bile ducts.
Primary biliary cirrhosis, a widespread, though uncommon, autoimmune
inflammatory
disease of bile ducts, is a disorder primarily affecting middle-aged and older
women. Secondary
biliary cirrhosis results from chronic obstruction or recurrent infection in
the extrahepatic bile
ducts caused by strictures, gallstones, or tumors. Infestation of the biliary
tract with a liver fluke,
Clonorchis sinensis, is a cause of secondary biliary cirrhosis in Asia.
Portal hypertension, the increased pressure in the portal vein and its
tributaries that is the
result of impediments to venous flow into the liver, is brought about by the
scarring characteristic
of the cirrhotic process. The increased pressure causes feeders of the portal
vein to distend
markedly, producing varices, or dilations of the veins. When varices are
located in supe~cial
tissues, they may rupture and bleed profusely. Two such locations are the
lower esophagus and the
perianal region. The accumulation of fluid in the abdominal cavity, or
ascites, is related to portal
hypertension, significant reduction in serum albumin, and renal retention of
sodium. When
albumin levels in blood are lower than normal, there is a marked reduction in
the force that holds
plasma water within the blood vessels and normally resists the effects of the
intravascular pressure.
The resulting increase in intravascular pressure, coupled with the increased
internal pressure
caused by the portal venous obstruction in the liver, leads to massive losses
of plasma water into
the abdominal cavity. The associated reduction of blood flow to the kidneys
causes increased
elaboration of the hormone aldosterone, which, in turn, causes the retention
of sodium and water
and a reduction in urinary output. In addition, because the movement of
intestinal lymph into the
liver is blocked by the cirrhotic process in the liver, the backflow of this
fluid into the abdominal
cavity is greatly increased. A progressive reduction in kidney function that
often occurs in persons
with advanced acute or chronic liver disease, hepatorenal syndrome, probably
results from an
inadequate perfusion of blood through the cortical (outer) portions of the
kidneys, where most
removal of waste products occurs. With advanced hepatocytic dysfunction, a
spasm of blood
vessels in the renal cortex can occur, often with good blood flow to the rest
of the kidney. This
spasm results in progressive failure in kidney function and often leads to
death.
Although not uncommon, cancer originating in the liver, usually in hepatocytes
and less
frequently in cells of bile duct origin, is rare in the West and is almost
always associated with
active cirrhosis, particularly the form found in patients with chronic
hepatitis. Long exposure to
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certain environmental poisons, such as vinyl chloride or carbon tetrachloride,
has also been shown
to lead to hepatic cancer. Cancers arising elsewhere in the body, particularly
in abdominal organs,
lungs, and lymphoid tissue, commonly lead to metastatic cancer in the liver
and are by far the most
frequent type of hepatic malignancy. Various benign types of tumors and cysts
arise from certain
components of the liver, such as the hepatocytes (adenomas) or blood vessels
(hemangiomas).
While the cause of these lesions is not always clear, hepatic adenomas are
associated with the
prolonged use of female sex hormones (estrogens). Benign cysts in the liver
may occur as
congenital defects or as the result of infections from infestation of the dog
tapeworm
(Echirzococcus granulosus). Abscesses on the liver result from the spread of
infection from the
biliary tract or from other parts of the body, especially the appendix and the
pelvic organs. Specific
liver abscesses also result from infections with the intestinal parasite
Entamoeba laistolytica.
Disorders of the Biliary Tract
Cholelithiasis, or the formation of gallstones in the gallbladder, is the most
common
disease of the biliary tract. There are three types of Gallstones: stones
containing primarily calcium
bilirubinate (pigment stones); stones containing 25 percent or more of
cholesterol; and stones
composed of variable mixtures of both bilirubin and cholesterol (mixed
gallstones). Pigment
stones are the result of an increased amount of bilirubin in the Liver (due to
hemolytic disease) and
the consequent secretion into the biliary tract of increased amounts of the
water-soluble conjugate,
bilirubin diglucuronide, a pigment that is normally secreted in the urine.
Cholesterol and mixed
cholesterol-bilirubinate stones occur when the proportion of cholesterol in
bile exceeds the
capacity of bile acids and lecithin to contain the total amount of cholesterol
in micellar colloidal
solution. Postcholecystectomy syndrome comprises painful attacks, often
resembling preoperative
symptoms, that occasionally occur following the surgical removal of gallstones
and the
gallbladder. These attacks may be related to intermittent muscular spasms of
the sphincter of Oddi
or of the bile ducts.
Cancer of the biliary tract is rare but may occur in almost any area,
including the
gallbladder, the hepatic ducts, the common bile duct, or the ampulla of Vater.
In cancer of the bile
duct, congenital cysts and parasitic infections, such as Liver flukes, seem to
lead to increased risks.
Persons with extensive chronic ulcerative colitis also show a greater than
normal incidence of bile
duct carcinoma.
Jaundice, or yellowing of the skin, scleras, and mucous membranes, occurs
whenever the
level of bilirubin in the blood is significantly above normal. This condition
is evident in three
different types of disorders including, unconjugated, or hemolytic, jaundice;
hepatocellular
jaundice; and cholestatic, or obstructive jaundice. Unconjugated jaundice
results when the amount
of bilirubin produced from hemoglobin by the destruction of red blood cells or
muscle tissue
(myoglobin) overwhelms the normal capacity of the liver to transport it or
when the ability of the
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liver to conjugate normal amounts of bilirubin into bilirubin diglucuronide is
significantly reduced
by inadequate intracellular transport or enzyme systems. Hepatocellular
jaundice arises when liver
cells are damaged so severely that their ability to transport bilirubin
diglucuronide into the biliary
system is reduced, allowing some of this yellow pigment to regurgitate into
the bloodstream.
Cholestatic jaundice, occurs when essentially normal liver cells are unable to
transport bilirubin
either through the hepatocytic-bile capillary membrane, because of damage in
that area, or through
the biliary tract, because of anatonnical obstructions (e.g., atresias,
gallstones, cancer).
Disorders of the Pancreas
Inflammation of the pancreas, or pancreatitis, is probably the most common
disease of this
organ. The disorder may be confined to either singular or repeated acute
episodes, or it may
become a chronic disease. There are many factors associated with the onset of
pancreatitis,
including direct injury, certain drugs, viral infections, heredity,
hyperlipidemia (increased levels of
blood fats), and congenital derangements of the ductal system. Localized,
severe abdominal and
midback pain resulting from enzyme leakage, tissue damage, and nerve irntation
is the most
common symptom of acute pancreatitis. In severe cases, respiratory failure,
shock, and even death
rnay occur. Chronic pancreatitis rarely follows repeated acute attacks. It
seems instead to be a
separate disorder that results in mucus plugs and precipitation of calcium
salts in the smaller
pancreatic ducts. Mucous production and plugging of the pancreas in Cystic
fibrosis patients
almost invariably causes destruction and scarring of the acinar tissue,
usually without damaging
the islets of Langerhans. A similar process in the hepatic biliary system
produces foci of fibrosis
and bile duct proliferation, a singular form of cirrhosis.
The discovery of new human digestive system associated polynucleotides, the
polypeptides encoded by them, and antibodies that immunospecifically bind
these polypeptides,
satisfies a need in the art by providing new compositions which are useful in
detecting, preventing,
diagnosing, prognosticating, treating, and/or ameliorating diseases and
disorders of the digestive
system, including, but not limited to, dysphagia, odynophagia, congenital
disorders of the
esophagus, gastric reflux, diverticula, Mallory-Weiss lesions, leiomyomas of
the esophagus,
lipoma, anorexia, nausea, ulcerative disease, pyloric stenosis,
gastroenteritis, gastritis, gastric
atropy, gastric cancer, benign tumors of the duodenum (e.g., polyps and
carcinoids), pancreatic
cancer, cancer of the bile duct, distension, irritable bowel syndrome,
malabsorption, congenital
disorders of the small intestine (e.g., Meckel's diverticulum, multiple
diverticula), bacterial and
parasitic infection (e.g., traveler's diarrhea, typhoid, paratyphoid, cholera,
roundworms,
tapeworms, amoebae, hookworms, strongyloides, threadworms, and blood flukes),
megacolon
(e.g., Hirschsprung's disease, aganglionic megacolon, acquired megacolon),
colitis (e.g., due to
bacterial, fungal, or parasitic infection, ulcerative colitis), tumors of the
colon (e.g., polyps or
cancers), anorectal disorders (e.g., anal fistulas, hemorrhoids, hepatitis
(e.g., acute, chronic,
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persistent hepatitis, viral (for example, hepatitis caused by hepatitis virus
A (HAV), hepatitis virus
B (HBV), and hepatitis virus non-A, non-B (NANB) infection), congenital
disorders of the liver
(e.g., Wilson's disease, hemochromatosis, cystic fibrosis, biliary atresia,
and alphal-antitrypsin
deficiency), cirrhosis, portal hypertension, cholelithiasis, cancer of the
biliary tract, jaundice (e.g.,
unconjugated, hemolytic, hepatocellular, cholestatic, or obstructive
jaundice).
The discovery of new human gastrointestinal-associated polynucleotides, the
polypeptides
encoded by them, and antibodies that immunospecifically bind these
polypeptides, satisfies a need
in the art by providing new compositions which are useful in detecting,
preventing, diagnosing,
prognosticating, treating, and/or ameliorating gastrointestinal-specific
diseases and disorders
described in more detail below.
Summary of the Invention
The present invention encompasses human secreted proteins/polypeptides, and
isolated
nucleic acid molecules encoding said proteins/polypeptides, useful for
detecting, preventing,
diagnosing, prognosticating, treating, and/or ameliorating gastrointestinal
diseases and disorders.
Antibodies that bind these polypeptides are also encompassed by the present
invention; as are
vectors, host cells, and recombinant and synthetic methods for producing said
polynucleotides,
polypeptides, and/or antibodies. The invention further encompasses screening
methods for
identifying agonists and antagonists of polynucleotides and polypeptides of
the invention. The
present invention also encompasses methods and compositions fox inhibiting or
enhancing the
production and function of the polypeptides of the present invention.
Detailed Description
Polynucleotides and Polyuentides of the Invention
Description of Table 1A
Table 1A summarizes information concerning certain polypnucleotides and
polypeptides
of the invention. The first column provides the gene number in the application
for each clone
identifier. The second column provides a unique clone identifier, "Clone ID:",
for a cDNA clone
related to each contig sequence disclosed in Table 1A. Third column, the cDNA
Clones identified
in the second column were deposited as indicated in the third column (i.e. by
ATCC Deposit No:Z
and deposit date). Some of the deposits contain multiple different clones
corresponding to the
same gene. In the fourth column, "Vector" refers to the type of vector
contained in the
corresponding cDNA Clone identified in the second column. In the fifth column,
the nucleotide
sequence identified as "NT SEQ m NO:X" was assembled from partially homologous
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("overlapping") sequences obtained from the corresponding cDNA clone
identified in the second
column and, in some cases, from additional related cDNA clones. The
overlapping sequences
were assembled into a single contiguous sequence of high redundancy (usually
three to five
overlapping sequences at each nucleotide position), resulting in a final
sequence identified as SEQ
)D NO:X. In the sixth column, "Total NT Seq." refers to the total number of
nucleotides in the
contig sequence identified as SEQ ID NO:X." The deposited clone may contain
aII or most of
these sequences, reflected by the nucleotide position indicated as "5' NT of
Clone Seq." (seventh
column) and the "3' NT of Clone Seq." (eighth column) of SEQ )D NO:X. In the
ninth column,
the nucleotide position of SEQ ID NO:X of the putative start codon
(methionine) is identified as
"5' NT of Start Codon." Similarly , in column ten, the nucleotide position of
SEQ ID NO:X of the
predicted signal sequence is identified as "5' NT of First AA of Signal Pep."
In the eleventh
column, the translated amino acid sequence, beginning with the methionine, is
identified as "AA
SEQ >D NO:Y," although other reading frames can also be routinely translated
using known
molecular biology techniques. The polypeptides produced by these alternative
open reading
frames are specifically contemplated by the present invention.
In the twelfth and thirteenth columns of Table 1A, the first and last amino
acid position of
SEQ ID NO:Y of the predicted signal peptide is identified as "First AA of Sig
Pep" and "Last AA
of Sig Pep." In the fourteenth column, the predicted first amino acid position
of SEQ ID NO:Y of
the secreted portion is identified as "Predicted First AA of Secreted
Portion". The amino acid
position of SEQ ID NO:Y of the last amino acid encoded by the open reading
frame is identified in
the fifteenth column as "Last AA of ORF".
SEQ >D NO:X (where X may be any of the polynucleotide sequences disclosed in
the
sequence listing) and the translated SEQ 1D NO:Y (where Y may be any of the
polypeptide
sequences disclosed in the sequence listing) are sufficiently accurate and
otherwise suitable for a
variety of uses well known in the art and described further below. For
instance, SEQ ID NO:X is
useful for designing nucleic acid hybridization probes that will detect
nucleic acid sequences
contained in SEQ )17 NO:X or the cDNA contained in the deposited clone. These
probes will also
hybridize to nucleic acid molecules in biological samples, thereby enabling a
variety of forensic
and diagnostic methods of the invention. Similarly, polypeptides identified
from SEQ ID NO:Y
may be used, for example, to generate antibodies which bind specifically to
proteins containing the
polypeptides and the secreted proteins encoded by the cDNA clones identified
in Table 1A and/or
elsewhere herein
Nevertheless, DNA sequences generated by sequencing reactions can contain
sequencing
errors. The errors exist as misidentified nucleotides, or as insertions or
deletions of nucleotides in
the generated DNA sequence. The erroneously inserted or deleted nucleotides
cause frame shifts
in the reading frames of the predicted amino acid sequence. In these cases,
the predicted amino
acid sequence diverges from the actual amino acid sequence, even though the
generated DNA
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sequence may be greater than 99.9% identical to the actual DNA sequence (for
example, one base
insertion or deletion in an open reading frame of over 1000 bases).
Accordingly, for those applications requiring precision in the nucleotide
sequence or the
amino acid sequence, the present invention provides not only the generated
nucleotide sequence
identified as SEQ ID NO:X, and the predicted translated amino acid sequence
identified as SEQ
ID NO:Y, but also a sample of plasmid DNA containing a human cDNA of the
invention
deposited with the ATCC, as set forth in Table 1A. The nucleotide sequence of
each deposited
plasmid can readily be determined by sequencing the deposited plasmid in
accordance with known
methods
The predicted amino acid sequence can then be verified from such deposits.
Moreover,
the amino acid sequence of the protein encoded by a particular plasmid can
also be directly
determined by. peptide sequencing or by expressing the protein in a suitable
host cell containing
the deposited human cDNA, collecting the protein, and determining its
sequence.
Also provided in Table 1A is the name of the vector which contains the cDNA
plasmid.
Each vector is routinely used in the art. The following additional information
is provided for
convenience.
Vectors Lambda Zap (U.S. Patent Nos. 5,128,256 and 5,286,636), Uni-Zap XR
(U.S.
Patent Nos. 5,128, 256 and 5,286,636), Zap Express (U.S. Patent Nos. 5,128,256
and 5,286,636),
pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res. 16:7583-7600
(1988); Alting-Mees, M.
A. and Short, J. M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Aping-Mees,
M. A. et al.,
Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning
Systems, Inc.,
11011 N. Torrey Pines Road, La Jolla, CA, 92037. pBS contains an ampicillin
resistance gene and
pBK contains a neomycin resistance gene. Phagemid pBS may be excised from the
Lambda Zap
and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express
vector. Both
phagemids may be transformed into E. coli strain XL-1 Blue, also available
from Stratagene
Vectors pSportl, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, were obtained
from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, MD 20897. All
Sport vectors contain
an ampicillin resistance gene and may be transformed into E. coli strain
DH10B, also available
from Life Technologies. See, for instance, Gruber, C. E., et al., Focus 15:59
(1993). Vector
lafmid BA (Bento Soares, Columbia University, New York, NY) contains an
ampicillin resistance
gene and can be transformed into E. coli strain XL-1 Blue. Vector pCR~2.1,
which is available
from Invitrogen, 1600 Faraday Avenue, Carlsbad, CA 92008, contains an
ampicillin resistance
gene and may be transformed into E. coli strain DH10B, available from Life
Technologies. See,
for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D.
et al.,
Biol1'eclanology 9: (1991).
The present invention also relates to the genes corresponding to SEQ ID NO:X,
SEQ ID
NO:Y, and/or a deposited cDNA (cDNA Clone ?D). The corresponding gene can be
isolated in
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accordance with known methods using the sequence information disclosed herein.
Such methods
include, but are not limited to, preparing probes or primers from the
disclosed sequence and
identifying or amplifying the corresponding gene from appropriate sources of
genomic material.
Also provided in the present invention are allelic variants, orthologs, and/or
species
homologs. Procedures known in the art can be used to obtain full-length genes,
allelic variants,
splice variants, full-length coding portions, orthologs, and/or species
homologs of genes
corresponding to SEQ ID NO:X and SEQ >D NO:Y using information from the
sequences
disclosed herein or the clones deposited with the ATCC. For example, allelic
variants and/or
species homologs may be isolated and identified by making suitable probes or
primers from the
sequences provided herein and screening a suitable nucleic acid source for
allelic variants and/or
the desired homologue. .
The present invention provides a polynucleotide comprising, or alternatively
consisting of,
the nucleic acid sequence of SEQ m NO:X and/or a cDNA contained in ATCC
Deposit No.Z.
The present invention also provides a polypeptide comprising, or
alternatively, consisting of, the
polypeptide sequence of SEQ m NO:Y, a polypeptide encoded by SEQ 1D NO:X,
and/or a
polypeptide encoded by a cDNA contained in ATCC deposit No.Z. Polynucleotides
encoding a
polypeptide comprising, or alternatively consisting of the polypeptide
sequence of SEQ m NO:Y,
a polypeptide encoded by SEQ ID NO:X and/or a polypeptide encoded by the cDNA
contained in
ATCC Deposit No.Z, are also encompassed by the invention. The present
invention further
encompasses a polynucleotide comprising, or alternatively consisting of the
complement of the
nucleic acid sequence of SEQ m NO:X, and/or the complement of the coding
strand of the cDNA
contained in ATCC Deposit No.Z. .
Description of Table 1B (Comprised of Tables 1B.1 and 1B.2)
Table 1B.1 and Table 1B.2 summarize some of the polynucleotides encompassed by
the invention (including cDNA clones related to the sequences (Clone ID:),
contig sequences
(contig identifier (Contig ID:) and contig nucleotide sequence identifiers
(SEQ ID NO:X)) and
further summarizes certain characteristics of these polynucleotides and the
polypeptides encoded
thereby. The first column of Tables 1B.1 and 1B.2 provide the gene numbers in
the application for
each clone identifier. The second column of Tables 1B.1 and 1B.2 provide
unique clone
identifiers, "Clone m:", for cDNA clones related to each contig sequence
disclosed in Table 1A
and/or Table 1B. The third column of Tables 1B.1 and 1B.2 provide unique
contig identifiers,
"Contig m:" for each of the ~ontig sequences disclosed in these tables. The
fourth column of
Tables IB.1 and 1B.2 provide the sequence identifiers, "SEQ )17 NO:X", for
each of the contig
sequences disclosed in Table 1A and/or 1B.
Table 1B.1
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The fifth column of Table 1B.1, "ORF (From-To)", provides the location (i.e.,
nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:X
that delineates
the preferred open reading frame (ORF) that encodes the amino acid sequence
shown in the
sequence listing and referenced in Table 1B.1 as SEQ ID NO:Y (column 6).
Column 7 of Table
1B.1 lists residues comprising predicted epitopes contained in the
polypeptides encoded by each of
the preferred ORFs (SEQ ID NO:Y). Identification of potential immunogenic
regions was
performed according to the method of Jameson and Wolf (CABIOS, 4; I81-186
(1988));
specifically, the Genetics Computer Group (GCG) implementation of this
algorithm, embodied in
the program PEPTIDESTRUCTURE (Wisconsin Package v10.0, Genetics Computer Group
(GCG), Madison, Wisc.). This method returns a measure of the probability that
a given residue is
found on the surface of the protein. Regions where the antigenic index score
is greater than 0.9
over at least 6 amino acids are indicated in Table 1B.1 as "Predicted
Epitopes". In particular
embodiments, polypeptides of the invention comprise, or alternatively consist
of, one, two, three,
four, five or more of the predicted epitopes described in Table 1B.1. It will
be appreciated that
depending on the analytical criteria used to predict antigenic determinants,
the exact address of the
determinant may vary slightly. Column 8 of Table 1B.1 ("Cytologic Band")
provides the
chromosomal location of polynucleotides corresponding to SEQ ID NO:X.
Chromosomal location
was determined by finding exact matches to EST and cDNA sequences contained in
the NCBI
(National Center for Biotechnology Information) UniGene database. Given a
presumptive
chromosomal location, disease locus association was determined by comparison
with the Morbid
Map, derived from Online Mendelian Inheritance in Man (Online Mendelian
Inheritance in Man,
OM1MTM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins
University
(Baltimore, MD) and National Center for Biotechnology Information, National
Library of
Medicine (Bethesda, MD) 2000. World Wide Web URL:
http://www.ncbi.nlm.nih.gov/omim/). If
the putative chromosomal location of the Query overlaps with the chromosomal
location of a
Morbid Map entry, an OMIM identification number is disclosed in Table 1B.1,
column 9 labeled
"OMIM Disease References)". A key to the OMI1VI reference identification
numbers is provided
in Table 5.
Table 1B.2
Column 5 of Table 1B.2, "Tissue Distribution" shows the expression profile of
tissue,
cells, and/or cell line libraries which express the polynucleotides of the
invention. The first code
number shown in Table 1B.2 column 5 (preceding the colon), represents the
tissue/cell source
identifier code corresponding to the key provided in Table 4. Expression of
these polynucleotides
was not observed in the other tissues and/or cell libraries tested. The second
number in column 5
(following the colon), represents the number of times a sequence corresponding
to the reference
polynucleotide sequence (e.g., SEQ ll~ NO:X) was identified in the
corresponding tissue/cell
source. Those tissue%ell source identifier codes in which the first two
letters are "AR" designate
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information generated using DNA array technology. Utilizing this technology,
cDNAs were
amplified by PCR and then transferred, in duplicate, onto the array. Gene
expression was assayed
through hybridization of first strand cDNA probes to the DNA array. cDNA
probes were generated
from total RNA extracted from a variety of different tissues and cell lines.
Probe synthesis was
performed in the presence of 33P dCTP, using oligo(dT) to prime reverse
transcription. After
hybridization, high stringency washing conditions were employed to remove non-
specific hybrids
from the array. The remaining signal, emanating from each gene target, was
measured using a
Phosphorimager. Gene expression was reported as Phosphor Stimulating
Luminescence (PSL)
which reflects the level of phosphor signal generated from the probe
hybridized to each of the gene
targets represented on the array. A local background signal subtraction was
performed before the
total signal generated from each array was used to normalize gene expression
between the
different hybridizations. The value presented after "[array code:" represents
the mean of the
duplicate values, following background subtraction and probe normalization.
One of skill in the
art could routinely use this information to identify normal and/or diseased
tissues) which show a
predominant expression pattern of the corresponding polynucleotide of the
invention or to identify
polynucleotides which show predominant and/or specific tissue and/or cell
expression.
Description of Table 1C
Table 1C summarizes additional polynucleotides encompassed by the invention
(including cDNA clones related to the sequences (Clone ID:), contig sequences
(contig identifier
(Contig ID:) contig nucleotide sequence identifiers (SEQ ID NO:X)), and
genomic sequences
(SEQ ID NO:B). The first column provides a unique clone identifier, "Clone
m:", for a cDNA
clone related to each contig sequence. The second column provides the sequence
identifier, "SEQ
)D NO:X", for each contig sequence. The third column provides a unique contig
identifier,
"Contig )D:" for each contig sequence. The fourth column, provides a BAC
identifier "BAC m
NO:A" for the BAC clone referenced in the corresponding row of the table. The
fifth column
provides the nucleotide sequence identifier, "SEQ m NO:B" for a fragment of
the BAC clone
identified in column four of the corresponding row of the table. The sixth
column, "Exon From-
To", provides the location (i.e., nucleotide position numbers) within the
polynucleotide sequence
of SEQ m NO:B which delineate certain polynucleotides of the invention that
are also exemplary
members of polynucleotide sequences that encode polypeptides of the invention
(e.g., polypeptides
containing amino acid sequences encoded by the polynucleotide sequences
delineated in column
six, and fragments and variants thereof).
Description of Table 1D
Table 1D: In preferred embodiments, the present invention encompasses a method
of
detecting, preventing, diagnosing, prognosticating, treating, and/or
ameliorating gastrointestinal
CA 02441397 2003-09-19
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diseases or disorders; comprising administering to a patient in which such
treatrrient, prevention,
or amelioration is desired a protein, nucleic acid, or antibody of the
invention (or fragment or
variant thereof) represented by Table IA, Table 1B, and Table 1C, in an amount
effective to
detect, prevent, diagnose, prognosticate, treat, and/or ameliorate the disease
or disorder.
As indicated in Table 1D, the polynucleotides, polypeptides, agonists, or
antagonists of the
present invention (including antibodies) can be used in assays to test for one
or more biological
activities. If these polynucleotides and polypeptides do exhibit activity in a
particular assay, it is
likely that these molecules may be involved in the diseases associated with
the biological activity.
Thus, the polynucleotides or polypeptides, or agonists or antagonists thereof
(including antibodies)
could be used to treat the associated disease.
Table 1D provides information related to biological activities for
polynucleotides and
polypeptides of the invention (including antibodies, agonists, and/or
antagonists thereof). Table
1D also provides information related to assays which may be used to test
polynucleotides and
polypeptides of the invention (including antibodies, agonists, and/or
antagonists thereof) for the
corresponding biological activities. The first column ("Gene No.") provides
the gene number in
the application for each clone identifier. The second column ("cDNA Clone
ll~:") provides the
unique clone identifier for each clone as previously described and indicated
in Tables 1A, 1B, and
1C. The third column ("AA SEQ ID NO:Y") indicates the Sequence Listing SEQ ID
Number for
polypeptide sequences encoded by the corresponding cDNA clones (also as
indicated in Tables
1A, 1B, and 2). The fourth column ("Biological Activity") indicates a
biological activity
corresponding to the indicated polypeptides (or polynucleotides encoding said
polypeptides). The
fifth column ("Exemplary Activity Assay") further describes the corresponding
biological activity
and provides information pertaining to the various types of assays which may
be performed to test,
demonstrate, or quantify the corresponding biological activity. Table 1D
describes the use of
FMAT technology, inter alia, for testing or demonstrating various biological
activities.
Fluorometric microvolume assay technology (FMAT) is a fluorescence-based
system which
provides a means to perform nonradioactive cell- and bead-based assays to
detect activation of cell
signal transduction pathways. This technology was designed specifically for
ligand binding and
immunological assays. Using this technology, fluorescent cells or beads at the
bottom of the well
are detected as localized areas of concentrated fluorescence using a data
processing system.
Unbound flurophore comprising the background signal is ignored, allowing for a
wide variety of
homogeneous assays. FMAT technology may be used for peptide ligand binding
assays,
immunofluorescence, apoptosis, cytotoxicity, and bead-based immunocapture
assays. See,
Miraglia S et. al., "Homogeneous cell and bead based assays for highthroughput
screening using
flourometric microvolume assay technology," Journal of Biomolecular Screening;
4:193-204
(1999). In particular, FMAT technology may be used to test, cnnfn-m, and/or
identify the ability of
polypeptides (including polypeptide fragments and variants) to activate signal
transduction
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pathways. For example, FMAT technology may be used to test, confirm, and/or
identify the
ability of polypeptides to upregulate production of immunomodulatory proteins
(such as, for
example, interleukins, GM-CSF, Rantes, and Tumor Necrosis factors, as well as
other cellular
regulators (e.g. insulin)).
Table 1D also describes the use of kinase assays fox testing, demonstrating,
or quantifying
biological activity. In this regard, the phosphorylation and de-
phosphorylation of specific amino
acid residues (e.g. Tyrosine, Serine, Threonine) on cell-signal transduction
proteins provides a fast,
reversible means for activation and de-activation of cellular signal
transduction pathways.
Moreover, cell signal transduction via phosphorylation/de-phosphorylation is
crucial to the
regulation of a wide variety of cellular processes (e.g. proliferation,
differentiation, migration,
apoptosis, etc.). Accordingly, kinase assays provide a powerful tool useful
for testing, confirming,
and/or identifying polypeptides (including polypeptide fragments and variants)
that mediate cell
signal transduction events via protein phosphorylation. See e.g., Forrer, P.,
Tamaskovic R., and
Jaussi, R. "Enzyme-Linked Immunosorbent Assay for Measurement of JNK, ERK, and
p38 Kinase
Activities" Biol. Chem. 379(8-9): 1101-1110 (1998).
Description of Table 2
Table 2 summarizes homology and features of some of the polypeptides of the
invention.
The first column provides a unique clone identifier, "Clone ID:",
corresponding to a cDNA clone
disclosed in Table 1A or Table 1B. The second column provides the unique
contig identifier,
"Contig 1D:" corresponding to contigs in Table 1B and allowing for correlation
with the
information in Table 1B. The third column provides the sequence identifier,
"SEQ ID NO:X", for
the contig polynucleotide sequence. The fourth column provides the analysis
method by which the
homology/identity disclosed in the Table was determined. Comparisons were made
between
polypeptides encoded by the polynucleotides of the invention and either a non-
redundant protein
database (herein referred to as "NR"), or a database of protein families
(herein referred to as
"PFAM") as further described below. The fifth column provides a description of
the PFAM/NR
hit having a significant match to a polypeptide of the invention. Column six
provides the
accession number of the PFAM/NR hit disclosed in the fifth column. Column
seven,
"Score/Percent Identity", provides a quality score or the percent identity, of
the hit disclosed in
columns five and six. Columns 8 and 9, "NT From" and "NT To" respectively,
delineate the
polynucleotides in "SEQ ID NO:X" that encode a polypeptide having a
significant match to the
PFAM/NR database as disclosed in the fifth and sixth columns. In specific
embodiments
polypeptides of the invention comprise, or alternatively consist of, an amino
acid sequence
encoded by a polynucleotide in SEQ 1D NO:X as delineated in columns 8 and 9,
or fragments or
variants thereof.
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Description of Table 3
Table 3 provides polynucleotide sequences that may be disclaimed according to
certain
embodiments of the invention. The first column provides a unique clone
identifier, "Clone )D",
for a cDNA clone related to contig sequences disclosed in Table 1B. The second
column provides
the sequence identifier, "SEQ ID NO:X", for contig sequences disclosed in
Table 1A and/or Table
1B. The third column provides the unique contig identifier, "Contig ID:", for
contigs disclosed in
Table 1B. The fourth column provides a unique integer 'a' where 'a' is any
integer between 1 and
the final nucleotide minus 15 of SEQ ID NO:X, and the fifth column provides a
unique integer 'b'
where 'b' is any integer between 15 and the final nucleotide of SEQ m NO:X,
where both a and b
correspond to the positions of nucleotide residues shown in SEQ m NO:X, and
where b is greater
than or equal to a + 14. For each of the polynucleotides shown as SEQ ID NO:X,
the uniquely
defined integers can be substituted into the general formula of a-b, and used
to describe
polynucleotides which may be preferably excluded from the invention. In
certain embodiments,
preferably excluded from the invention are at least one, two, three, four,
five, ten, or more of the
polynucleotide sequences) having the accession numbers) disclosed in the sixth
column of this
Table (including for example, published sequence in connection with a
particular BAC clone). In
further embodiments, preferably excluded from the invention are the specific
polynucleotide
sequences) contained in the clones corresponding to at least one, two, three,
four, f ve, ten, or
more of the available material having the accession numbers identified in the
sixth column of this
Table (including for example, the actual sequence contained in an identified
BAC clone).
Description of Table 4
Table 4 provides a key to the tissue/cell source identifier code disclosed in
Table 1B.2,
column 5. Column 1 of Table 4 provides the tissue/cell source identifier code
disclosed in Table
1B.2, Column 5. Columns 2-5 provide a description of the tissue or cell
source. Note that
"Description" and "Tissue" sources (i.e. columns 2 and 3) having the prefix
"a_" indicates organs,
tissues, or cells derived from "adult" sources. Codes corresponding to
diseased tissues are
indicated in column 6 with the word "disease." The use of the word "disease"
in column 6 is non-
limiting. The tissue or cell source may be specific (e.g. a neoplasm), or may
be disease-associated
(e.g., a tissue sample from a normal portion of a diseased organ).
Furthermore, tissues and/or cells
lacking the "disease" designation may still be derived from sources directly
or indirectly involved
in a disease state or disorder, and therefore may have a further utility in
that disease state or
disorder. In numerous cases where the tissue/cell source is a library, column
7 identifies the vector
used to generate the library.
Description of Table 5
Table 5 provides a key to the OMIM reference identification numbers disclosed
in Table
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1B.1, column 9. OMIM reference identification numbers (Column 1) were derived
from Oxiline
Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OM1M.
McKusick-Nathans
Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and
National Center
for Biotechnology Information, National Library of Medicine, (Bethesda, MD)
2000. World Wide
Web URL: http://www.ncbi.nlm.nih.gov/omim/). Column 2 provides diseases
associated with the
cytologic band disclosed in Table 1B.1, column ~, as determined using the
Morbid Map database.
Description of Table 6
Table 6 summarizes some of the ATCC Deposits, Deposit dates, and ATCC
designation
numbers of deposits made with the ATCC in connection with the present
application. These
deposits were made in addition to those described in the Table 1A.
Description of Table 7
Table 7 shows the cDNA libraries sequenced, and ATCC designation numbers and
vector
information relating to these cDNA libraries.
The first column shows the first four letters indicating the Library from
which each library
clone was derived. The second column indicates the catalogued tissue
description for the
corresponding libraries. The third column indicates the vector containing the
corresponding
clones. The fourth column shows the ATCC deposit designation for each libray
clone as indicated
by the deposit information in Table 6.
Definitions
The following definitions are provided to facilitate understanding of certain
terms used
throughout this specification.
In the present invention, "isolated" refers to material removed from its
original
environment (e.g., the natural environment if it is naturally occurring), and
thus is altered "by the
hand of man" from its natural state. For example, an isolated polynucleotide
could be part of a
vector or a composition of matter, or could be contained within a cell, and
still be "isolated"
because that vector, composition of matter, or particular cell is
not°the original environment of the
polynucleotide. The term "isolated" does not refer to genomic or eDNA
libraries, whole cell total
or mRNA preparations, genomic DNA preparations (including those separated by
electrophoresis
and transferred onto blots), sheared whole cell genomic DNA preparations or
other compositions
where the art demonstrates no distinguishing features of the
polynucleotide/sequences of the
present invention.
In 'the present invention, a "secreted" protein refers to those proteins
capable of being
directed to the ER, secretory vesicles, or the extracellular space as a result
of a signal sequence, as
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well as those proteins released into the extracellular space without
necessarily containing a signal
sequence. If the secreted protein is released into the extracellular space,
the secreted protein can
undergo extracellular processing to produce a "mature" protein. Release into
the extracellular
space can occur by many mechanisms, including exocytosis and proteolytic
cleavage.
As used herein, a "polynucleotide" refers to a molecule having a nucleic acid
sequence
encoding SEQ ID NO:Y or a fragment or variant thereof (e.g., the polypeptide
delinated in
columns fourteen and fifteen of Table 1A); a nucleic acid sequence contained
in SEQ ID NO:X (as
described in column 5 of Table 1A and/or column 3 of Table 1B) or the
complement thereof; a
cDNA sequence contained in Clone ID: (as described in column 2 of Table 1A
and/or Table 1B
and contained within a library deposited with the ATCC); a nucleotide sequence
encoding the
polypeptide encoded by a nucleotide, sequence in SEQ ID NO:B as defined in
column 6 (EXON
From-To) of Table 1C or a fragment or variant thereof; or a nucleotide coding
sequence in SEQ ID
NO:B as defined in column 6 of Table 1C or the complement thereof. For
example, the
polynucleotide can contain the nucleotide sequence of the full length cDNA
sequence, including
the 5' and 3' untranslated sequences, the coding region, as well as fragments,
epitopes, domains,
and variants of the nucleic acid sequence. Moreover, as used herein, a
"polypeptide" refers to a
molecule having an amino acid sequence encoded by a polynucleotide of the
invention as broadly
defined (obviously excluding poly-Phenylalanine or poly-Lysine peptide
sequences which result
from translation of a polyA tail of a sequence corresponding to a cDNA).
In the present invention, "SEQ m NO:X" was often generated by overlapping
sequences
contained in multiple clones (contig analysis). A representative clone
containing all or most of the
sequence for SEQ ID NO:X is deposited at Human Genome Sciences, Inc. (HGS) in
a catalogued
and archived library. As shown, for example, in column 2 of Table 1B, each
clone is identified by
a cDNA Clone ID (identifier generally referred to herein as Clone >D:). Each
Clone ID is unique to
an individual clone and the Clone ID is all the information needed to retrieve
a given clone from
the HGS library. Table 7 provides a list of the deposited cDNA libraries. One
can use the Clone
JD: to determine the library source by reference to Tables 6 and 7. Table 7
lists the deposited
cDNA libraries by name and links each library to an ATCC Deposit. Library
names contain four
characters, fox example, "HTWE." The name of a cDNA clone (Clone ID) isolated
from that
library begins with the same four characters, for example "HTWEP07". As
mentioned below,
Table 1A and/or Table 1B correlates the Clone ID names with SEQ ID NO:X. Thus,
starting with
an SEQ ID NO:X, one can use Tables 1A, 1B, 6, 7, and 9 to determine the
corresponding Clone
ID, which library it came from and which ATCC deposit the library is contained
in. Furthermore,
it is possible to retrieve a given cDNA clone from the source library by
techniques known in the
art and described elsewhere herein. The ATCC is located at 1001 University
Boulevard,
Manassas, Virginia 20110-2209, USA. The ATCC deposits were made pursuant to
the terms of the
CA 02441397 2003-09-19
WO 02/076488 PCT/US02/08276
Budapest Treaty on the international recognition of the deposit of
microorganisms for the purposes
of patent procedure.
In specific embodiments, the polynucleotides of the invention are at least 15,
at least 30, at
least 50, at least 100, at least 125, at least 500, or at least 1000
continuous nucleotides but are less
than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5kb, 5 kb, 2.5
kb, 2.0 kb, or 1 kb, in
length. In a further embodiment, polynucleotides of the invention comprise a
portion of the
coding sequences, as disclosed herein, but do not comprise all or a portion of
any intron. In
another embodiment, the polynucleotides comprising coding sequences do not
contain coding
sequences of a genomic flanking gene (i.e., 5' or 3' to the gene of interest
in the genome). In other
embodiments, the polynucleotides of the invention do not contain the coding
sequence of more
than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic
flanking gene(s).
A "polynucleotide" of the present invention also includes those
polynucleotides capable of
hybridizing, under stringent hybridization conditions, to sequences contained
in SEQ )D NO:X, or
the complement thereof (e.g., the complement of any one, two, three, four, or
more of the
polynucleotide fragments described herein), the polynucleotide sequence
delineated in columns 7
and 8 of Table 1A or the complement thereof, the polynucleotide sequence
delineated in columns
8 and 9 of Table 2 or the complement thereof, and/or cDNA sequences contained
in Clone m:
(e.g., the complement of any one, two, three, four, or more of the
polynucleotide fragments, or the
cDNA clone within the pool of cDNA clones deposited with the ATCC, described
herein), and/or
the polynucleotide sequence delineated in column 6 of Table 1C or the
complement thereof.
"Stringent hybridization conditions" refers to an overnight incubation at 42
degree C in a solution
comprising 50% formamide, 5x SSC (750 mM NaCI, 75 mM trisodium citrate), 50 mM
sodium
phosphate (pH 7.6), 5x Denhardt's solution, 10% dextran sulfate, and 20 ~,g/ml
denatured, sheared
salmon sperm DNA, followed by washing the filters in O.lx SSC at about 65
degree C.
Also contemplated are nucleic acid molecules that hybridize to the
polynucleotides of the
present invention at lower stringency hybridization conditions. Changes in the
stringency of
hybridization and signal detection are primarily accomplished through the
manipulation of
formamide concentration (lower percentages of formamide result in lowered
stringency); salt
conditions, or temperature. For example, lower stringency conditions include
an overnight
incubation at 37 degree C in a solution comprising 6X SSPE (20X SSPE = 3M
NaCI; 0.2M
NaH2P04; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide, 100 ug/ml salmon sperm
blocking
DNA; followed by washes at 50 degree C with 1XSSPE, 0.1% SDS. In addition, to
achieve even
lower stringency, washes performed following stringent hybridization can be
done at higher salt
concentrations (e.g. 5X SSC).
Note that variations in the above conditions may be accomplished through the
inclusion
and/or substitution of alternate blocking reagents used to suppress background
in hybridization
experiments. Typical blocking reagents include Denhardt's reagent, BLOTTO,
heparin, denatured
21
CA 02441397 2003-09-19
WO 02/076488 PCT/US02/08276
salmon sperm DNA, and commercially available proprietary formulations. The
inclusion of
specific blocking reagents may require modification of the hybridization
conditions described
above, due to problems with compatibility.
Of course, a polynucleotide which hybridizes only to polyA+ sequences (such as
any 3'
terminal polyA+ tract of a cDNA shown in the sequence listing), or to a
complementary stretch of
T (or ~ residues, would not be included in the definition of "polynucleotide,"
since such a
polynucleotide would hybridize to any nucleic acid molecule containing a poly
(A) stretch or the
complement thereof (e.g., practically any double-stranded cDNA clone generated
using oligo dT
as a primer).
The polynucleotide of the present invention can be composed of any
polyribonucleotide or
polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or
DNA. For
example, polynucleotides can be composed of single- and double-stranded DNA,
DNA that is a
mixture of single- and double-stranded regions, single- and double-stranded
RNA, and RNA that
is mixture of single- and double-stranded regions, hybrid molecules comprising
DNA and RNA
that may be single-stranded or, more typically, double-stranded or a mixture
of single- and double-
stranded regions. In addition, the polynucleotide can be composed of triple-
stranded regions
comprising RNA or DNA or both RNA and DNA. A polynucleotide may also contain
one or
more modified bases or DNA or RNA backbones modified for stability or for
other reasons.
"Modified" bases include, for example, tritylated bases and unusual bases such
as inosine. A
variety of modifications can be made to DNA and RNA; thus, "polynucleotide"
embraces
chemically, enzymatically, or metabolically modified forms.
In specific embodiments, the polynucleotides of the invention are at least 15,
at least 30, at
least 50, at least 100, at least 125, at least 500, or at least 1000
continuous nucleotides but are less
than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.5kb, 5 kb, 2.5
kb, 2.0 kb, or 1 kb, in
length. In a further embodiment, polynucleotides of the invention comprise a
portion of the
coding sequences, as disclosed herein, but do not comprise all or a portion of
any intron. In
another embodiment, the polynucleotides comprising coding sequences do not
contain coding
sequences of a genomic flanking gene (i.e., 5' or 3' to the gene of interest
in the genome). In other
embodiments, the polynucleotides of the invention do not contain the coding
sequence of more
than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic
flanking gene(s).
"SEQ >D NO:X" refers to a polynucleotide sequence described in column 5 of
Table 1A,
while "SEQ m NO:Y" refers to a polypeptide sequence described in column 10 of
Table 1A. SEQ
ID NO:X is identified by an integer specified in column 6 of Table 1A. The
polypeptide sequence
SEQ ID NO:Y is a translated open reading frame (ORF) encoded by polynucleotide
SEQ )D
NO:X. The polynucleotide sequences are shown in the sequence listing
immediately followed by
all of the polypeptide sequences. Thus, a polypeptide sequence corresponding
to polynucleotide
sequence SEQ m N0:2 is the first polypeptide sequence' shown in the sequence
listing. The
22
CA 02441397 2003-09-19
WO 02/076488 PCT/US02/08276
second polypeptide sequence corresponds to the polynucleotide sequence shown
as SEQ ID N0:3,
and so on.
The polypeptide of the present invention can be composed of amino acids joined
to each
other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and
may contain amino
acids other than the 20 gene-encoded amino acids. The polypeptides may be
modified by either
natural processes, such as posttranslational processing, or by chemical
modification techniques
which are well known in the art. Such modifications are well described in
basic texts and in more
detailed monographs, as well as in a voluminous research literature.
Modifications can occur
anywhere in a polypeptide, including the peptide backbone, the amino acid side-
chains and the
amino or carboxyl termini. It will be appreciated that the same type of
modification may be
present in the same or varying degrees at several sites in a given
polypeptide. Also, a given
polypeptide may contain many types of modifications. Polypeptides may be
branched, for
example, as a result of ubiquitination, and they may be cyclic, with or
without branching. Cyclic,
branched, and branched cyclic polypeptides may result from posttranslation
natural processes or
I5 may be made by synthetic methods. Modifications include acetylation,
acylation, ADP-
ribosylation, amidation, covalent attachment of flavin, covalent attachment of
a heme moiety,
covalent attachment of a nucleotide or nucleotide derivative, covalent
attachment of a lipid or lipid
derivative, covalent attaclnnent of phosphotidylinositol, cross-linking,
cyclization, disulfide bond
formation, demethylation, formation of covalent cross-links, formation of
cysteine, formation of
pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor
formation,
hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation,
proteolytic
processing, phosphorylation, prenylation, racemization, selenoylation,
sulfation, transfer-RNA
mediated addition of amino acids to proteins such as arginylation, and
ubiquitination. (See, for
instance, PROTEINS - STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E.
Creighton, W. H. Freeman and Company, New York (1993); POSTTRANSLATIONAL
COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New
York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646 (1990);
Rattan et al., Ann.
N.Y. Acad. Sci. 663:48-62 (1992)).
"SEQ ID NO:X" refers to a polynucleotide sequence described, for example, in
Tables 1A,
Table 1B, or Table 2, while "SEQ ID NO:Y" refers to a polypeptide sequence
described in column
11 of Table 1A and or column 6 of Table 1B.1. SEQ ID NO:X is identified by an
integer specified
in column 4 of Table 1B. The polypeptide sequence SEQ ID NO:Y is a translated
open reading
frame (ORF) encoded by polynucleotide SEQ ID NO:X. "Clone ID:" refers to a
cDNA clone
described in column 2 of Table 1A andlor 1B.
"A polypeptide having functional activity" refers to a polypeptide capable of
displaying
one or more known functional activities associated with a full-length
(complete) protein. Such
functional activities include, but are not limited to, biological activity
(e.g. activity useful in
23
CA 02441397 2003-09-19
WO 02/076488 PCT/US02/08276
treating, preventing and/or ameliorating gastrointestinal diseases and
disorders), antigenicity
(ability to bind [or compete with a polypeptide for binding] to an anti-
polypeptide antibody),
immunogenicity (ability to generate antibody which binds to a specific
polypeptide of the
invention), ability to form multimers with polypeptides of the invention, and
ability to bind to a
receptor or ligand for a polypeptide.
The polypeptides of the invention can be assayed for functional activity (e.g.
biological
activity) using or routinely modifying assays known in the art, as well as
assays described herein.
Specifically, one of skill in the art may routinely assay secreted
polypeptides (including fragments
and variants) of the invention for activity using assays as described in the
examples section below.
"A polypeptide having biological activity" refers to a polypeptide exhibiting
activity
similar to, but not necessarily identical to, an activity of a polypeptide of
the present invention,
including mature forms, as measured in a particular biological assay, with or
without dose
dependency. In the case where dose dependency does exist, it need not be
identical to that of the
polypeptide, but rather substantially similar to the dose-dependence in a
given activity as
compared to the polypeptide of the present invention (i.e., the candidate
polypeptide will exhibit
greater activity or not more than about 25-fold less and, preferably, not more
than about tenfold
less activity, and most preferably, not more than about three-fold less
activity relative to the
polypeptide of the present invention).
TABLES:
Table 1A
Table 1A summarizes information concerning certain polypnucleotides and
polypeptides
of the invention. The first column provides the gene number in the application
for each clone
identifier. The second column provides a unique clone identifier, "Clone )D:",
for a cDNA clone
related to each contig sequence disclosed in Table 1A. Third column, the cDNA
Clones identified
in the second column were deposited as indicated in the third column (i.e. by
ATCC Deposit No:Z
and deposit date). Some of the deposits contain multiple different clones
corresponding to the
same gene. In the fourth column, "Vector" refers to the type of vector
contained in the
corresponding cDNA Clone identified in the second column. In the fifth column,
the nucleotide
sequence identified as "NT SEQ 1D NO:X" was assembled from partially
homologous
("overlapping") sequences obtained from the corresponding cDNA clone
identified in the second
column and, in some cases, from additional related cDNA clones. The
overlapping sequences
were assembled into a single contiguous sequence of high redundancy (usually
three to five
overlapping sequences at each nucleotide position), resulting in a final
sequence identified as SEQ
)D NO:X. In the sixth column, "Total NT Seq." refers to the total number of
nucleotides in the
contig sequence identified as SEQ m NO:X." The deposited clone may contain all
or most of
these sequences, reflected by the nucleotide position indicated as "5' NT of
Clone Seq." (seventh
24
CA 02441397 2003-09-19
WO 02/076488 PCT/US02/08276
column) and the "3' NT of Clone Seq." (eighth column) of SEQ 1D NO:X. In the
ninth column,
the nucleotide position of SEQ ID NO:X of the putative start codon
(methionine) is identified as
"5' NT of Start Codon." Similarly , in column ten, the nucleotide position of
SEQ )D NO:X of the
predicted signal sequence is identified as "5' NT of First AA of Signal Pep."
In the eleventh
column, the translated amino acid sequence, beginning with the methionine, is
identified as "AA
SEQ )17 NO:Y," although other reading frames can also be routinely translated
using known
molecular biology techniques. The polypeptides produced by these alternative
open reading
frames are specifically contemplated by the present invention.
In the twelfth and thirteenth columns of Table 1A, the first and last amino
acid position of
SEQ 117 NO:Y of the predicted signal peptide is identified as "First AA of Sig
Pep" and "Last AA
of Sig Pep." In the fourteenth column, the predicted first amino acid position
of SEQ m NO:Y of
the secreted portion is identified as "Predicted First AA of Secreted
Portion". The amino acid
position of SEQ m NO:Y of the last amino acid encoded by the open reading
frame is identified in
the fifteenth column as "Last AA of ORF".
SEQ m NO:X (where X may be any of the polynucleotide sequences disclosed in
the
sequence listing) and the translated SEQ m NO:Y (where Y may be any of the
polypeptide
sequences disclosed in the sequence listing) are sufficiently accurate and
otherwise suitable for a
variety of uses well lrnown in the art and described further below. For
instance, SEQ ID NO:X is
useful for designing nucleic acid hybridization probes that will detect
nucleic acid sequences
contained in SEQ )D NO:X or the cDNA contained in the deposited clone. These
probes will also
hybridize to nucleic acid molecules in biological samples, thereby enabling a
variety of forensic
and diagnostic methods of the invention. Similarly, polypeptides identified
from SEQ )D NO:Y
may be used, for example, to generate antibodies which bind specifically to
proteins containing the
polypeptides and the secreted proteins encoded by the cDNA clones identified
in Table 1A and/or
elsewhere herein
Nevertheless, DNA sequences generated by sequencing reactions can contain
sequencing
errors. The errors exist as misidentified nucleotides, or as insertions or
deletions of nucleotides in
the generated DNA sequence. The erroneously inserted or deleted nucleotides
cause frame shifts
in the reading frames of the predicted amino acid sequence. In these cases,
the predicted amino
acid sequence diverges from the actual amino acid sequence, even though the
generated DNA
sequence may be greater than 99.9% identical to the actual DNA sequence (for
example, one base
insertion or deletion in an open reading frame of over 1000 bases).
Accordingly, for those applications requiring precision in the nucleotide
sequence or the
amino acid sequence, the present invention provides not only the generated
nucleotide sequence
identified as SEQ m NO:X, and the predicted translated amino acid sequence
identified as SEQ
ID NO:Y, but also a sample of plasmid DNA containing a human cDNA of the
invention
deposited with the ATCC, as set forth in Table 1A. The nucleotide sequence of
each deposited
CA 02441397 2003-09-19
WO 02/076488 PCT/US02/08276
plasmid can readily be determined by sequencing the deposited plasmid in
accordance with known
methods
The predicted amino acid sequence can then be verified from such deposits.
Moreover,
the amino acid sequence of the protein encoded by a particular plasmid can
also be directly
determined by peptide sequencing or by expressing the protein in a suitable
host cell containing
the deposited human cDNA, collecting the protein, and determining its
sequence.
Also provided in Table 1A is the name of the vector which contains the cDNA
plasmid.
Each vector is routinely used in the art. The following additional information
is provided for
convenience.
Vectors Lambda Zap (U.S. Patent Nos. 5,128,256 and 5,286,636), Uni-Zap XR
(U.S.
Patent Nos. 5,128, 256 and 5,286,636), Zap Express (U.S. Patent Nos. 5,128,256
and 5,286,636),
pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res. 16:7583-7600
(1988); Alting-Mees, M.
A. and Short, J. M., Nucleic Acids Res. 17:9494 (1989)) and pBK (Alting-Mees,
M. A. et al.,
Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning
Systems, Inc.,
11011 N. Torrey Pines Road, La Jolla, CA, 92037. pBS contains an ampicillin
resistance gene and
pBK contains a neomycin resistance gene. Phagemid pBS may be excised from the
Lambda Zap
and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express
vector. Both
phagemids may be transformed info E. coli strain XL-1 Blue, also available
from Stratagene
Vectors pSportl, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, were obtained
from Life Technologies, Inc., P. O. Box 6009, Gaithersburg, MD 20897. All
Sport vectors contain
ari ampicillin resistance gene and may be transformed into E. coli strain
DH10B, also available
from Life Technologies. See, for instance, Gruber, C. E., et al., Focus 15:59
(1993). Vector
lafmid BA (Bento Soares, Columbia University, New York, NY) contains an
ampicillin resistance
gene and can be transformed into E. coli strain XL-1 Blue. Vector
pCR°2.1, which is available
from Invitrogen, 1600 Faraday Avenue, Carlsbad, CA 92008, contains an
ampicillin resistance
gene and may be transformed into E. coli strain DH10B, available from Life
Technologies. See,
for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D.
et al.,
BiolTechnology 9: (1991).
The present invention also relates to the genes corresponding to SEQ m NO:X,
SEQ m
NO:Y, and/or a deposited cDNA (cDNA Clone )~). The corresponding gene can be
isolated in
accordance with known methods using the sequence information disclosed herein.
Such methods
include, but are not limited to, preparing probes or primers from the
disclosed sequence and
identifying or amplifying the corresponding gene from appropriate sources of
genomic material.
Also provided in the present invention are allelic variants, orthologs, andlor
species
homologs. Procedures known in the art can be used to obtain full-length genes,
allelic variants,
splice variants, full-Iength coding portions, orthologs, and/or species
homologs of genes
corresponding to SEQ ID NO:X and SEQ m NO:Y using information from the
sequences
26
CA 02441397 2003-09-19
WO 02/076488 PCT/US02/08276
disclosed herein or the clones deposited with the ATCC. For example, allelic
variants and/or
species homologs may be isolated and identified by making suitable probes or
primers from the
sequences provided herein and screening a suitable nucleic acid source for
allelic variants and/or
the desired homologue.
The present invention provides a polynucleotide comprising, or alternatively
consisting of,
the nucleic acid sequence of SEQ >D NO:X and/or a cDNA contained in ATCC
Deposit No.Z.
The present invention also provides a polypeptide comprising, or
alternatively, consisting of, the
polypeptide sequence of SEQ )D NO:Y, a polypeptide encoded by SEQ >D NO:X,
andlor a
polypeptide encoded by a cDNA contained in ATCC deposit No.Z. Polynucleotides
encoding a
polypeptide comprising, or alternatively consisting of the polypeptide
sequence of SEQ m NO:Y,
a polypeptide encoded by SEQ m NO:X and/or a polypeptide encoded by the cDNA
contained in
ATCC Deposit No.Z, are also encompassed by tfie invention. The present
invention further
encompasses a polynucleotide comprising, or alternatively consisting of the
complement of the
nucleic acid sequence of SEQ >D NO:X, and/or the complement of the coding
strand of the cDNA
contained in ATCC Deposit No.Z.
27
CA 02441397 2003-09-19
WO 02/076488 PCT/US02/08276
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CA 02441397 2003-09-19
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29
CA 02441397 2003-09-19
WO 02/076488 PCT/US02/08276
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CA 02441397 2003-09-19
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CA 02441397 2003-09-19
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CA 02441397 2003-09-19
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CA 02441397 2003-09-19
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CA 02441397 2003-09-19
WO 02/076488 PCT/US02/08276
Table 1B (Comprised of Tables 1B.1 and 1B.2)
The first column in Table IB.1 and Table 1B.2 provides the gene number in the
application corresponding to the clone identifier. The second column in Table
1B.1 and Table 1B.2
provides a unique "Clone ID:" for the cDNA clone related to each contig
sequence disclosed in Table
1B.1 and Table 1B.2. This clone ID references the cDNA clone which contains at
least the 5' most
sequence of the assembled contig and at least a portion of SEQ ID NO:X as
determined by directly
sequencing the referenced clone. The referenced clone may have more sequence
than described in the
sequence listing or the clone may have less. In the vast majority of cases,
however, the clone is
believed to encode a full-length polypeptide. In the case where a clone is not
full-length, a full-length
LO cDNA can be obtained by methods described elsewhere herein. The third
column in Table 1B.1 and
Table 1B.2 provides a unique "Contig ID" identification for each contig
sequence. The fourth column
in Table 1B.1 and Table 1B.2 provides the "SEQ 1D NO:" identifier for each of
the contig
polynucleotide sequences disclosed in Table 1B.
Table 1B.1
The fifth column in Table 1B.1, "ORF (From-To)", provides the location (i.e.,
nucleotide
position numbers) within the polynucleotide sequence "SEQ ID NO:X" that
delineate the preferred
open reading frame (ORF) shown in the sequence listing and referenced in Table
1B.1, column 6, as
SEQ m NO:Y. Where the nucleotide position number "To" is lower than the
nucleotide position
number "From", the preferred ORF is the reverse complement of the referenced
polynucleotide
sequence. The sixth column in Table 1B.1 provides the corresponding SEQ ID
NO:Y for the
polypeptide sequence encoded by the preferred ORF delineated in column 5. In
one embodiment, the
invention provides an amino acid sequence comprising, or alternatively
consisting of, a polypeptide
encoded by the portion of SEQ ID NO:X delineated by "ORF (From-To)". Also
provided are
polynucleotides encoding such amino acid sequences and the complementary
strand thereto. Column
7 in Table 1B.1 lists residues comprising epitopes contained in the
polypeptides encoded by the
preferred ORF (SEQ ID NO:Y), as predicted using the algorithm of Jameson and
Wolf, (1988) Comp.
Appl. Biosci. 4:181-186. The Jameson-Wolf antigenic analysis was performed
using the computer
program PROTEAN (Version 3.11 for the Power Macintosh, DNASTAR, Inc., 1228
South Park
Street Madison, WI). In specific embodiments, polypeptides of the invention
comprise, or
alternatively consist of, at least one, two, three, four, five or more of the
predicted epitopes as
described in Table 1B. It will be appreciated that depending on the analytical
criteria used to predict
antigenic determinants, the exact address of the determinant may vary
slightly.
Column 8 in Table 1B.1 provides a chromosomal map location for certain
polynucleotides of the invention. Chromosomal location was determined by
finding exact matches to
CA 02441397 2003-09-19
WO 02/076488 PCT/US02/08276
EST and cDNA sequences contained in the NCBI (National Center for
Biotechnology Information)
UniGene database. Each sequence in the UniGene database is assigned to a
"cluster"; all of the ESTs,
cDNAs, and STSs in a cluster are believed to be derived from a single gene.
Chromosomal mapping
data is often available for one or more sequences) in a UniGene cluster; this
data (if consistent) is
then applied to the cluster as a whole. Thus, it is possible to infer the
chromosomal location of a new
polynucleotide sequence by determining its identity with a mapped UniGene
cluster.
A modified version of the computer program BLASTN (Altshul, et al., J. Mol.
Biol.
215:403-410 (1990), and Gish, and States, Nat. Genet. 3:266-272) (1993) was
used to search the
UniGene database for EST or cDNA sequences that contain exact or near-exact
matches to a
l0 polynucleotide sequence of the invention (the 'Query'). A sequence from the
UniGene database (the
'Subject') was said to be an exact match if it contained a segment of 50
nucleotides in length such that
48 of those nucleotides were in the same order as found in the Query sequence.
If all of the matches
that met this criteria were in the same UniGene cluster, and mapping data was
available for this
cluster, it is indicated in Table 1B under the heading "Cytologic Band". Where
a cluster had been
L5 further localized to a distinct cytologic band, that band is disclosed;
where no banding information
was available, but the gene had been localized to a single chromosome, the
chromosome is disclosed.
Once a presumptive chromosomal location was determined for a polynucleotide of
the
invention, an associated disease locus was identified by comparison with a
database of diseases which
have been experimentally associated with genetic loci. The database used was
the Morbid Map,
derived from OMIMTM and National Center for Biotechnology Information,
National Library of
Medicine (Bethesda, MD) 2000;. If the putative chromosomal location of a
polynucleotide of the
invention (Query sequence) was associated with a disease in the Morbid Map
database, an OMIM
reference identification number was noted in column 9, Table 1B.1, labelled
"OMIM Disease
Reference(s). Table 5 is a lcey to the OMIM reference identification numbers
(column 1), and
Z5 provides a description of the associated disease in Column 2.
Table 1B.2
Column 5, in Table 1B.2, provides an expression profile and library code:count
for each of
the contig sequences (SEQ ID NO:X) disclosed in Table 1B, which can routinely
be combined with
the information provided in Table 4 and used to determine the tissues, cells,
and/or cell line libraries
30 which predominantly express the polynucleotides of the invention. The first
number in Table 1B.2,
column 5 (preceding the colon), represents the tissue/cell source identifier
code corresponding to the
code and description provided in Table 4. The second number in column 5
(following the colon)
represents the number of times a sequence corresponding to the reference
polynucleotide sequence
was identified in the corresponding tissue/cell source. Those tissue/cell
source identifier code$ in
CA 02441397 2003-09-19
WO 02/076488 PCT/US02/08276
which the first two letters are "AR" designate information generated using DNA
array technology.
Utilizing this technology, cDNAs were amplified by PCR and then transferred,
in duplicate, onto the
array. Gene expression was assayed through hybridization of first strand cDNA
probes to the DNA
array. cDNA probes were generated from total RNA extracted from a variety of
different tissues and
cell lines. Probe synthesis was performed in the presence of 33P dCTP, using
oligo (dT) to prime
reverse transcription. After hybridization, high stringency washing conditions
were employed to
remove non-specific hybrids from the array. The remaining signal, emanating
from each gene target,
was measured using a Phosphorimager. Gene expression was reported as Phosphor
Stimulating
Luminescence (PSL) which reflects the level of phosphor signal generated from
the probe hybridized
l0 to each of the gene targets represented on the array. A local background
signal subtraction was
performed before the total signal generated from each array was used to
normalize gene expression
between the different hybridizations. The value presented after "[array
codej:" represents the mean of
the duplicate values, following background subtraction and probe
normalization. One of skill in the
art could routinely use this information to identify normal and/or diseased
tissues) which show a
predominant expression pattern of the corresponding polynucleotide of the
invention or to identify
polynucleotides which show predominant andlor specific tissue and/or cell
expression.
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~ N
l~ .~ O O ~~ N ri ,~ ~ ~ d~ O~ In O v0 Ov M N N d' ~ ~ O M ~ O oo N N ~~ V1 N
v0 wn oo v0 ~ Iw0 in O Ov O ~ oo O~ d' d~ ,--W ~ ~ oo v0 00 00 ~n o0
N ~ O ~ N ~ ~ N ~--~ N M M ~ N N ~, N N ~ N ~ N ~ ~ O
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N ~ ~ M .~ ~ ~ ~ ~ M ~ 00 1W p Sri ~n ~Y ~I" M M N ~' Vi ~'Y M M M N N N ~ N
O '~ '~ .~ V7 N ~ '-~ "'~ '.'1 I~ M O N I~ m m N 'd~ O O~ tn ~ ~ N O~ N ~ N o0
d- ~D ~ Oi
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M vp ~ M O r, O ~ N N N ~ N M ~ N M N ~ ~ O M
N r; ,~ M ~ ~,j ,-~ N ~ ,.._; ~ ~~ ~ I~ v0 ~O vi ~t ~t M M N ~ N Vi ~d~ d: M M
N N N ~ M
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N N ~ O N ~ ~p ~ ~ ~ ~ N ~~ M ~ N N ~ N O N O N O ~ N .-i .-~
O O O O ~p O O
-i ,-~ N N ,--i .-i
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141
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142
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Table 1C summarizes additional polynucleotides encompassed by the invention
(including cDNA clones related to the sequences (Clone ID:), contig sequences
(contig identifier
(Contig ID:) contig nucleotide sequence identifiers (SEQ ID NO:X)), and
genomic sequences
(SEQ ID NO:B). The first column provides a unique clone identifier, "Clone
ID:", for a cDNA
clone related to each contig sequence. The second column provides the sequence
identifier, "SEQ
ID NO:X", for each contig sequence. The third column provides a unique contig
identifier,
"Contig ll~:" for each contig sequence. The fourth column, provides a BAC
identifier "BAC ID
NO:A" for the BAC clone referenced in the corresponding row of the table. The
fifth column
provides the nucleotide sequence identifier, "SEQ ID NO:B" for a fragment of
the BAC clone
identified in column four of the corresponding row of the table. The sixth
column, "Exon From-
To", provides the location (i.e., nucleotide position numbers) within the
polynucleotide sequence
of SEQ ID NO:B which delineate certain polynucleotides of the invention that
are also exemplary
members of polynucleotide sequences that encode polypeptides of the invention
(e.g., polypeptides
containing amino acid sequences encoded by the polynucleotide sequences
delineated in column
six, and fragments and variants thereof).
TahlP 1 (~'.
cDNA CloneSEQ ID CONTIG BAC ID: SEQ ID EXON
ID NO:X ID: A NO:B From-To
HAUAI83 22 639009 AC010422 589 1-326
1552-2084
2162-2261
2300-2427
4485-5868
5948-6362
7914-8017
8569-8681
8765-8875
8968-9037
9284-9499
9742-9910
10837-11187
11271-11321
11554-11707
11783-12766
12866-13225
13256-13827
14284-14367
14890-15090
HAUAI83 22 639009 AC018761 590 1-326
1176-1284
1552-2084
2162-2261
2300-2426
4485-5868
143
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5948-6362
8569-8681
8765-8875
8968-9037
9284-9499
9742-9910
10317-10501
10837-11187
11271-11321
11554-11707
11783-12766
12866-13225
13256-13827
14284-14367
14890-15090
HAUAI83 22 639009 AC010422 591 1-315
2004-2289
2650-2741
3554-3830
HAUAI83 22 639009 AC010422 592 1-202
93 8-1047
I2I9-1395
1758-1956
2907-3429
3792-3935
5366-5485
6391-6688
6899-7269
7890-8316
8400-8524
8607-8682
8824-8999
9190-9302
9691-9796
10106-10177
10571-11051
11164-11490
12565-12696
13364-13501
13964-14592
14740-15540
15610-15798
15947-16642
16717-16832
16968-17408
17521-17612
18331-18579
19120-19303
19358-19514
19599-19702
20003-20245
HAUAI83 22 639009 AC018761 593 1-202
938-1047
1219-1395
1758-1956
144
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2907-3429
3792-3935
5366-5485
6391-6688
6899-7269
7591-7711
7890-8316
8400-8524
8607-8682
8749-9073
9190-9302
9691-9796
HAUAI83 22 639009 AC018761 594 1-82
128-293
1178-1447
1986-2278
2457-2711
3543-3844
HB1NS58 26 1352386 AL096774 595 1-1023
2010-2239
2581-2962
3153-3223
3324-3493
3973-4126
HBINS58 26 1352386 AL096774 596 1-341
HBINS58 26 1352386 AL096774 597 1-142
HCE3G69 29 728432 AC068946 598 1-108
1186-1324
1746-1835
2138-2284
2448-2545
2718-2861
3091-5889
HCE3G69 29 728432 AC068946 599 1-191
HCE3G69 29 728432 AC068946 600 1-686
HCEFB80 31 1143407 AL022327 601 1-2271
3506-3658
4643-4810
9039-9164
9382-9509
10587-10720
11135-11195
11265-11716
14644-15466
17451-17526
18012-18114
20530-20632
20957-21009
23696-23785
25338-25575
25969-26166
HCNDR47 34 1016919 AL122003 602 1-236
531-696
787-817
145
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g63-4508
5158-5744
6949-7029
HCNDR47 34 1016919 AL122003 603 1-888
1304-2003
2830-3284
3719-4571
4618-5268
6131-6557
8947-9033
9058-9726
14176-14480
18456-18915
18960-19871
22365-22454
23082-23248
28058-28215
HDPGT01 44 771583 AC020978 604 1-180
2776-2899
3916-4077
4296-4335
4436-4632
4895-5181
8153-8246
9547-9666
9907-10007
10370-10618
10788-11046
11926-13423
13465-13494
13764-15689
HDPGT01 44 771583 AC020978 605 1-384
HI~PSB18 50 1043263 AL355512 606 1-2572
3049-3871
HDPSB 18 50 1043263 AC006176 607 1-2571
3048-3872
HDPSB18 50 ' 1043263 AL355512 608 1-280
HI~PXY01 55 879048 AL354000 609 1-1319
4848-4975
5229-5600
6561-6654
HDPXY01 55 879048 AL035362 610 1-1316
4844-4971
5225-5596
6557-6650
HDPXY01 55 879048 AL354000 611 1-4.60
HDPXY01 55 879048 AL354000 612 1-400
HDPXY01 55 879048 AL035362 613 1-400
HDPXY01 55 879048 .AL035362 614 1-460
HHGCG53 80 340818 AC024037 615 1-518
HHGCM76 81 662329 AC003665 616 1-70
304-609
900-1090
1240-1835
146
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2272-2490
2581-3598
HHGCM76 81 662329 AC003665 617 1-580
851-995
1224-1296
1314-1663
1930-1975
2724-2905
2968-3098
3283-3328
5121-5230
5331-5689
HJACG30 84 895505 AC018512 618 1-776
HJACG30 84 895505 AC022305 619 1-878
HJACG30 84 895505 AC002518 620 1-150
HLTIP94 105 1087335 AC007431 621 1-1299
HLTIP94 105 1087335 AC007431 622 1-330
HMSDL37 115 973996 AC012086 623 1-3328
HMSDL37 115 973996 AC018811 624 1-3051
HMSDL37 115 973996 AC018494 625 1-3029
HMSDL37 115 973996 AC012086 626 1-224
HMSDL37 115 973996 AC012086 627 1-468
HMSDL37 115 973996 AC018811 628 1-222
HMSDL37 115 973996 AC018811 629 1-468
HMSDL37 115 973996 AC018494 630 1-224
HMSDL37 115 973996 AC018494 631 1-1854
HNGOI12 128 1041375 AC003675 632 1-2128
HNGOIl2 128 1041375 AC001228 633 1-2129
HNGOI12 128 1041375 AC013791 634 1-2132
I~IiFMl4 130 664507 AC020552 635 1-290
HNI~'M14 130 664507 AC020552 636 1-96
HPJBK12 147 1011467 AC022033 637 1-2649
HI'JBK12 147 1011467 AC013541 638 1-2649
HPJBKl2 147 1011467 AC022033 639 1-190
HPJBK12 147 1011467 AC013541 640 1-190
HPRAL78 149 1352342 AC007783 641 1-2334
2508-3084
3578-3890
4198-4294
4376-4623
4712-5349
5369-6088
6527-7107
7298-7392
7730-7846
9147-9476
10487-10575
10791-11298
11485-11601
11783-13009
13207-13501
13540-13772
14439-14800
14923-14983
147
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15133-15355
15485-15653
16750-16805
16894-17078
17162-17219
18003-18089
21085-21146
21358-21501
HPRAL78 149 1352342 AC007783 642 1-308
HPRAL78 149 1352342 AC007783 643 1-1024
HRGBL78 153 910133 AL359541 644 1-254
2777-3307
3670-3823
4113-4385
4844-5381
5995-7365
HSAWD74 156 460527 AC004951 645 1-1651
1740-2593
HSAWD74 256 460527 AC004952 646 1-149
HSAWD74 156 460527 AC004951 647 1-5057
5082-8353
8404-8996
HTPCS72 177 854941 AL008639 648 1-106
1457-1595
1666-2484
2910-3006
3705-4147
4768-5141
5304-5536
5746-S
874
7114-7241
7468-7711
7963-8746
943 8-12408
12884-14976
HTPCS72 177 854941 AL008639 649 1-720
HTPIH83 178 919916 AL158821 6S0 1-1862
1880-3126
Tables 1D: The polynucleotides or polypeptides, or agonists or antagonists of
the present
invention can be used in assays to test for one or more biological activities.
If these
polynucleotides and polypeptides do exhibit activity in a particular assay, it
is likely that these
molecules may be involved in the diseases associated with the biological
activity. Thus, the
polynucleotides or polypeptides, or agonists or antagonists could be used to
treat the associated
disease.
The present invention encompasses methods of detecting, preventing,
diagnosing,
prognosticating, treating, and/or ameliorating a disease or disorder. In
preferred embodiments, the
present invention encompasses a method of treating a gastrointestinal disease
or disorder
148
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WO 02/076488 PCT/US02/08276
comprising administering to a patient in which such detection, treatment,
prevention, and/or
amelioration is desired a protein, nucleic acid, or antibody of the invention
(or fragment or variant
thereof) in an amount effective to detect, prevent, diagnose, prognosticate,
treat, and/or ameliorate
the gastrointestinal disease or disorder.
In another embodiment, the present invention also encompasses methods of
detecting,
preventing, diagnosing, prognosticating, treating, andlor ameliorating a
gastrointestinal disease or
disorder; comprising administering to a patient combinations of the proteins,
nucleic acids, or
antibodies of the invention (or fragments or variants thereof), sharing
similar indications as shown
in the corresponding rows in Column 3 of Table 1D.
Table 1D provides information related to biological activities for
polynucleotides and
polypeptides of the invention (including antibodies, agonists, and/or
antagonists thereof). Table
1D also provides information related to assays which may be used to test
polynucleotides and
polypeptides of the invention (including antibodies, agonists, and/or
antagonists thereof) for the
corresponding biological activities. The first column ("Gene No.") provides
the gene number in
the application for each clone identifier. The second column ("cDNA Clone
ID:") provides the
unique clone identifier for each clone as previously described and indicated
in Table 1A through
Table 1D. The third column ("AA SEQ ID NO:Y") indicates the Sequence Listing
SEQ ID
Number for polypeptide sequences encoded by the corresponding cDNA clones
(also as indicated
in Tables 1A, Table 1B, and Table 2). The fourth column ("Biological
Activity") indicates a
biological activity corresponding to the indicated polypeptides (ox
polynucleotides encoding said
polypeptides). The fifth column ("Exemplary Activity Assay") further describes
the corresponding
biological activity and also provides information pertaining to the various
types of assays which
may be performed to test, demonstrate, or quantify the corresponding
biological activity.
Table 1D describes the use of, inter alia, FMAT technology for testing or
demonstrating
various biological activities. Fluorometric microvolume assay technology
(FMAT) is a
fluorescence-based system which provides a means to perform nonradioactive
cell- and bead-
based assays to detect activation of cell signal transduction pathways. This
technology was
designed specifically for ligand binding and immunological assays. Using this
technology,
fluorescent cells or beads at the bottom of the well are detected as localized
areas of concentrated
fluorescence using a data processing system. Unbound flurophore comprising the
background
signal is ignored, allowing for a wide variety of homogeneous assays. FMAT
technology may be
used for peptide ligand binding assays, immunofluorescence, apoptosis,
cytotoxicity, and bead-
based immunocapture assays. See, Miraglia S et. aL, "Homogeneous cell and bead
based assays
for highthroughput screening using flourometric microvolume assay technology,"
Journal of
Biomolecular Screening; 4;193-204 (1999). In particular, FMAT technology may
be used to test,
149
CA 02441397 2003-09-19
WO 02/076488 PCT/US02/08276
confirm, andlor identify the ability of polypeptides (including polypeptide
fragments and variants)
to activate signal transduction pathways. For example, FMAT technology may be
used to test,
confirm, and/or identify the ability of polypeptides to upregulate production
of immunomodulatory
proteins (such as, for example, interleukins, GM-CSF, Rantes, and Tumor
Necrosis factors, as well
as other cellular regulators (e.g. insulin)).
Table 1D also describes the use of kinase assays for testing, demonstrating,
or quantifying
biological activity. In this regard, the phosphorylation and de-
phosphorylation of specific amino
acid residues (e.g. Tyrosine, Serine, Threonine) on cell-signal transduction
proteins provides a fast,
reversible means for activation and de-activation of cellular signal
transduction pathways.
Moreover, cell signal transduction via phosphorylation/de-phosphorylation is
crucial to the
regulation of a wide variety of cellular processes (e.g. proliferation,
differentiation, migration,
apoptosis, etc.). Accordingly, kinase assays provide a powerful tool useful
for testing, confirming,
and/or identifying polypeptides (including polypeptide fragments and variants)
that mediate cell
signal transduction events via protein phosphorylation. See e.g., Forrer, P.,
Tamaskovic R., and
Jaussi, R. "Enzyme-Linked Immunosorbent Assay for Measurement of JNK, ERK, and
p38 Kinase
Activities" Biol. Chem. 379(8-9): 1101-1110 (1998).
150
CA 02441397 2003-09-19
WO 02/076488 PCT/US02/08276
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DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
CECI EST LE TOME 1 DE 6
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