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CA 02441840 2003-09-22
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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 proteins/polypeptides, useful for detecting,
preventing, diagnosing,
prognosticating, treating, and/or ameliorating cardiovascular diseases,
disorders, and/or conditions
related thereto. 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 cardiovascular system is a component of a complex physiological network
involved in maintaining the oxygen and nutrient supply to tissues of the body.
The heart is the anatomical and functional centerpiece of the cardiovascular
system.
Weighing only 250-350 grams (less than a pound), the heart is one of our
strongest and hardest
working organs. It is composed of innervated muscle tissue with unique
properties; e.g., it can
pace itself in contraction. The main center of rhythm regulation is the
sinoatrial (SA) node. Certain
cardiac cells repeatedly fire impulses that trigger heart contractions. These
autorhythmic cells have
two important functions. One is to act as a pacemaker (set the pace for the
entire heart), and the
other is to form a conduction system, the route for conducting impulses
throughout the heart
muscle. This conduction system controls the pattern of blood flow through the
heart.
The heart pumps at least five quarts of blood through a full circuit of the
body every
minute. The heart consists of two pumps, side by side. The pump on the right
side moves blood to
the lungs, where waste gases, such as carbon dioxide, are removed and oxygen
is added. Freshly
oxygenated blood returns to the pump on the left side, which moves it out into
the rest of the body.
Blood flows away from the heart to the lungs or to the rest of your body,
though blood
vessels called arteries. Arteries branch extensively, each branch become
smaller, forming blood
vessels called arterioles. Arterioles also become repeatedly smaller and
smaller until they are tiny
vessels called capillaries. Throughout the arteries and smaller vessels that
stem from them, the
blood delivers nutrients and oxygen to the tissues and picks up waste. This
task is completed in the
capillaries. As the blood moves on through the capillaries the blood vessels
gradually become
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larger, eventually becoming veins. Veins ultimately carry blood back to the
heart. The cycle then
begins again.
Disorders of the cardiovascular system are many and varied, killing more
Americans
each year than any other category of disorders. For example, damage to the
conduction system
leads to arrhythmia, an irregular beating of the heart. If left untreated, the
heart becomes unable to
effectively pump blood, frequently leading to permanent heart damage and/or
cardiac arrest.
One of the most prevalent conditions in industrialized countries today is
atherosclerosis. Atherosclerosis is the buildup of fatty deposits in the
intima of large and medium-
sized arteries. The buildup of deposits narrowing of the arteries, reducing or
potentially blocking
the ability of blood to flow through the arteries. ,Untreated, atherosclerosis
typically results in
cardiac arrest and, frequently, death.
Clearly, the discovery of new human cardiovascular-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
the diagnosis,
treatment, prevention and/or prognosis of caridovascular disorders.
Cardiovascular disorders include, but are not limited to, stroke,
cardiovascular
abnormalities, such as arterio-arterial fistula, arteriovenous fistula,
cerebral arteriovenous
malformations, congenital heart defects, pulmonary atresia, and Scimitar
Syndrome. Congenital
heart defects include, but are not limited to, aortic coarctation, cor
triatriatum, coronary vessel
anomalies, crisscross heart, dextrocardia, patent ductus arteriosus, Ebsteiri
s anomaly, Eisenmenger
complex, hypoplastic left heart syndrome, levocardia, tetralogy of fallot,
transposition of great
vessels, double outlet right ventricle, tricuspid atresia, persistent truncus
arteriosus, and heart
septal defects, such as aortopulmonary septal defect, endocardial cushion
defects, Lutembacher's
Syndrome, trilogy of Fallot, ventricular heart septal defects.
Cardiovascular disorders also include, but are not limited to, heart disease,
such as
arrhythmias, carcinoid heart disease, high cardiac output, low cardiac output,
cardiac tamponade,
endocarditis (including bacterial), heart aneurysm, cardiac arrest, congestive
heart failure,
congestive cardiomyopathy, paroxysmal dyspnea, cardiac edema, heart
hypertrophy, congestive
cardiomyopathy, left ventricular hypertrophy, right ventricular hypertrophy,
post-infarction heart
rupture, ventricular septal rupture, heart valve diseases, myocardial
diseases, myocardial ischemia,
pericardial effusion, pericarditis (including constrictive and tuberculous),
pneumopericardium,
postpericardiotomy syndrome, pulmonary heart disease, rheumatic heart disease,
ventricular
dysfunction, hyperemia, cardiovascular pregnancy complications, Scimitar
Syndrome,
cardiovascular syphilis, and cardiovascular tuberculosis.
Arrhythmias include, but are not limited to, sinus arrhythmia, atrial
fibrillation, atrial
flutter, bradycardia, extrasystole, Adams-Stokes Syndrome, bundle-branch
block, sinoatrial block,
long QT syndrome, parasystole, Lown-Ganong-Levine Syndrome, Mahaim-type pre-
excitation
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syndrome, Wolff-Parkinson-White syndrome, sick sinus syndrome, tachycardias,
and ventricular
fibrillation. Tachycardias include paroxysmal tachycardia, supraventricular
tachycardia,
accelerated idioventricular rhythm, atrioventricular nodal reentry
tachycardia, ectopic atrial
tachycardia, ectopic functional tachycardia, sinoatrial nodal reentry
tachycardia, sinus tachycardia,
Torsades de Pointes, and ventricular tachycardia.
Heart valve diseases include, but are not limited to, aortic valve
insufficiency, aortic
valve stenosis, hear murmurs, aortic valve prolapse, mitral valve prolapse,
tricuspid valve
prolapse, mitral valve insufficiency, mitral valve stenosis, pulmonary
atresia, pulmonary valve
insufficiency, pulmonary valve stenosis, tricuspid atresia, tricuspid valve
insufficiency, and
tricuspid valve stenosis.
Myocardial diseases include, but are not limited to, alcoholic cardiomyopathy,
congestive cardiomyopathy, hypertrophic cardiomyopathy, aortic subvalvular
stenosis, pulmonary
subvalvular stenosis, restrictive cardiomyopathy, Chagas cardiomyopathy,
endocardial
fibroelastosis, endomyocardial fibrosis, Kearns Syndrome, myocardial
reperfusion injury, and
myocarditis.
Myocardial ischemias include, but are not limited to, coronary disease, such
as angina
pectoris, coronary aneurysm, coronary arteriosclerosis, coronary thrombosis,
coronary vasospasm,
myocardial infarction and myocardial stunning.
Cardiovascular diseases also include vascular diseases such as aneurysms,
angiodysplasia, angiomatosis, bacillary angiomatosis, Hippel-Lindau Disease,
Klippel-Trenaunay-
Weber Syndrome, Sturge-Weber Syndrome, angioneurotic edema, aortic diseases,
Takayasu's
Arteritis, aortitis, Leriche's Syndrome, arterial occlusive diseases,
arteritis, enarteritis, polyarteritis
nodosa, cerebrovascular disorders, diabetic angiopathies, diabetic
retinopathy, embolisms,
thrombosis, erythromelalgia, hemorrhoids, hepatic veno-occlusive disease,
hypertension,
hypotension, ischemia, peripheral vascular diseases, phlebitis, pulmonary veno-
occlusive disease,
Raynaud's disease, CREST syndrome, retinal vein occlusion, Scimitar syndrome,
superior vena
cava syndrome, telangiectasia, atacia telangiectasia, hereditary hemorrhagic
telangiectasia,
varicocele, varicose veins, varicose ulcer, vasculitis, and venous
insufficiency.
Aneurysms include, but are not limited to, dissecting aneurysms, false
aneurysms,
infected aneurysms, ruptured aneurysms, aortic aneurysms, cerebral aneurysms,
coronary
aneurysms, heart aneurysms, and iliac aneurysms.
Arterial occlusive diseases include, but are not limited to, arteriosclerosis,
intermittent
claudication, carotid stenosis, fibromuscular dysplasias, mesenteric vascular
occlusion, Moyamoya
disease, renal artery obstruction, retinal artery occlusion, and
thromboangiitis obliterans.
Cerebrovascular disorders include, but are not limited to, carotid artery
diseases,
cerebral amyloid angiopathy, cerebral aneurysm, cerebral anoxia, cerebral
arteriosclerosis, cerebral
arteriovenous malformation, cerebral artery diseases, cerebral embolism and
thrombosis, carotid
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artery thrombosis, sinus thrombosis, Wallenberg's syndrome, cerebral
hemorrhage, epidural
hematoma, subdural hematoma, subaraxhnoid hemorrhage, cerebral infarction,
cerebral ischemia
(including transient), subclavian steal syndrome, periventricular
leukomalacia, vascular headache,
cluster headache, migraine, and vertebrobasilar insufficiency.
Embolisms include, but are not limited to, air embolisms, amniotic fluid
embolisms,
cholesterol embolisms, blue toe syndrome, fat embolisms, pulmonary embolisms,
and
thromoboembolisms. Thrombosis include, but are not limited to, coronary
thrombosis, hepatic
vein thrombosis, retinal vein occlusion, carotid artery thrombosis, sinus
thrombosis, Wallenberg's
syndrome, and thrombophlebitis.
Ischemic disorders include, but are not limited to, cerebral ischemia,
ischemic colitis,
compartment syndromes, anterior compartment syndrome, myocardial ischemia,
reperfusion
injuries, and peripheral limb ischemia. Vasculitis includes, but is not
limited to, aortitis, arteritis,
Behcet's Syndrome, Churg-Strauss Syndrome, mucocutaneous lymph node syndrome,
thromboangiitis obliterans, hypersensitivity vasculitis, Schoenlein-Henoch
purpura, allergic
cutaneous vasculitis, and Wegener s granulomatosis.
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 cardiovascular
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 for inhibiting or
enhancing the
production and function of the polypeptides of the present invention.
Detailed Description
Polynucleotides and Polvuentides 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
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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 ID 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 ID NO:X. In the sixth column, "Total NT Seq." refers to the total number
of nucleotides in
the contig sequence identified as SEQ >D 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
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 >D
NO:Y of the secreted portion is identified as "Predicted First AA of Secreted
Portion". The amino
acid position of SEQ )D 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 ID NO:X (where X may be any of the polynucleotide sequences disclosed in
the
sequence listing) and the translated SEQ )D 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 >D NO:X is
useful for designing nucleic acid hybridization probes that will detect
nucleic acid sequences
contained in SEQ ID 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
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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 >D 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
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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 >D NO:X,
SEQ
>D NO:Y, and/or a deposited cDNA (cDNA Clone )D). 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, 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 m 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 >Z7 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,
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 >D 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 the invention. The present
invention further
encompasses a polynucleotide comprising, or alternatively consisting of the
complement of the
nucleic acid sequence of SEQ >I7 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 )D:),
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
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identifiers, "Clone ID:", 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 ll~:" for each of the contig sequences disclosed in these tables. The
fourth column of
Tables 1B.1 and 1B.2 provide the sequence identifiers, "SEQ ID NO:X", for each
of the contig
sequences disclosed in Table 1A and/or 1B.
Table 1B.1
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; 181-186
(1988));
specifically, the Genetics Computer Group (GCG) implementation of this
algorithm, embodied in
the program PEPT>DESTRUCTURE (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,
OMIMTM. 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 OMIM reference identification numbers
is provided
in Table 5.
Table 1B.2
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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 m NO:X) was identified in the corresponding
tissue/cell
source. Those tissue/cell source identifier codes in which the first two
letters are "AR" designate
information generated using DNA array technology. Utilizing this technology,
cDNAs were
1.0 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 )D:), contig sequences
(contig identifier
(Contig >D:) contig nucleotide sequence identifiers (SEQ m NO:X)), and genomic
sequences
(SEQ m 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 >l7:" for each contig sequence. The fourth column, provides a BAC
identifier "BAC ll~
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-
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To", provides the location (i.e., nucleotide position numbers) within the
polynucleotide sequence
of SEQ >D 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 ID: In preferred embodiments, the present invention encompasses a method
of
detecting, preventing, diagnosing, prognosticating, treating, and/or
ameliorating cardiovascular
diseases or disorders; comprising administering to a patient in which such
treatment, prevention,
or amelioration is desired a protein, nucleic acid, or antibody of the
invention (or fragment or
variant thereof) represented by Table 1A, 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 ID, 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
ID 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
)D:") provides the
unique clone identifier for each clone as previously described and indicated
in Tables IA, 1B, and
1C. The third column ("AA SEQ 117 NO:Y") indicates the Sequence Listing SEQ )D
Number for
polypeptide sequences encoded by the corresponding cDNA clones (also as
indicated in Tables
IA, 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
CA 02441840 2003-09-22
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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, confirm, and/or
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).
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 >D:",
corresponding to a
cDNA clone disclosed in Table 1A or Table 1B. The second column provides the
unique contig
identifier, "Contig ID:" corresponding to contigs in Table 1B and allowing for
correlation with the
information in Table 1B. The third column provides the sequence identifier,
"SEQ >D 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
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"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 )D 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 ID NO:X as delineated in columns 8 and 9,
or fragments or
variants thereof.
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 >D NO:X", for contig sequences disclosed in
Table 1A and/or Table
1B. The third column provides the unique contig identifier, "Contig 1D:", 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 >I7 NO:X, and the fifth column provides a
unique integer 'b'
where 'b' is any integer between 15 and the final nucleotide of SEQ )D NO:X,
where both a and b
correspond to the positions of nucleotide residues shown in SEQ ID NO:X, and
where b is greater
than or equal to a + 14. For each of the polynucleotides shown as SEQ )D 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, five, 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 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"
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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 1B.1. OMIM reference identification numbers (Column 1) were derived from
Online
Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIM.
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, 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.
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In the present invention, "isolated" refers to material removed from its
original
environment (e.g., the natural environment if it is naturally occurnng), 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 cDNA
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
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 extracelhzlar
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 LD NO:Y or a fragment or variant thereof (e.g., the polypeptide
delinated in
columns fourteen and fifteen of Table IA); a nucleic acid sequence contained
in SEQ LD NO:X (as
described in column 5 of Table 1A and/or Table 1B) or the complement thereof;
a cDNA sequence
contained in Clone LD: (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 LD 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 ID 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 Table 1B, each
clone is identified by a
cDNA Clone ID (identifier generally referred to herein as Clone )D:). Each
Clone )D is unique to
an individual clone and the Clone )D is all the information needed to retrieve
a given clone from
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the HGS library. Table 7 provides a list of the deposited cDNA libraries. One
can use the Clone
>D: 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, for example, "HTWE." The name of a cDNA clone (Clone )D) 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 >D names with SEQ 1D NO:X. Thus,
starting with
an SEQ m 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 10801 University
Boulevard,
Manassas, Virginia 20110-2209, USA. The ATCC deposits were made pursuant to
the terms of the
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 D7: (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
p,g/ml denatured, sheared salmon sperm DNA, followed by washing the filters in
O. lx SSC at
about 65 degree C.
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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 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 U) 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, SO kb, 15 kb, 10 kb, 7.Skb,
5 kb, 2.5 kb, 2.0 kb, or
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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 ID 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 )D NO:X is identified by an integer specified in column 6 of Table 1A. The
polypeptide
sequence SEQ >D NO:Y is a translated open reading frame (ORF) encoded by
polynucleotide SEQ
ID 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 ID N0:2 is the first polypeptide sequence shown in the sequence
listing. The
second polypeptide sequence corresponds to the polynucleotide sequence shown
as SEQ >D 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
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 attachment 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.
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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 )D NO:X" refers to a polynucleotide sequence described, for example, in
Tables
1A, Table 1B, or Table 2, while "SEQ >D NO:Y" refers to a polypeptide sequence
described in
column 11 of Table 1A and or Table 1B. SEQ )D NO:X is identified by an integer
specified in
Table 1B. The polypeptide sequence SEQ II7 NO:Y is a translated open reading
frame (ORF)
encoded by polynucleotide SEQ 1T7 NO:X. "Clone 1D:" refers to a cDNA clone
described in
column 2 of Table 1A and/or Table 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
treating, preventing and/or ameliorating cardiovascular 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
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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 IA. 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 )D 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 m 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 all 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 >D 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 m 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 IA, the first and last amino
acid position
of SEQ m 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 ll~
NO:Y of the secreted portion is identified as "Predicted First AA of Secreted
Portion". The amino
acid position of SEQ )D 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 ll~ 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 )D 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
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polypeptides and the secreted proteins encoded by the cDNA clones identified
in Table 1A andlor
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 m 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.5.
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 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
CA 02441840 2003-09-22
WO 02/095010 PCT/US02/09785
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.,
Bio/lechnology 9: (1991).
The present invention also relates to the genes corresponding to SEQ >D NO:X,
SEQ
)D NO:Y, and/or a deposited cDNA (cDNA Clone )D). 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, 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 >17 NO:X and SEQ m 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 1D 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,
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 )D NO:Y,
a polypeptide encoded by SEQ )D 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 )D NO:X, and/or the complement of the coding
strand of the cDNA
contained in ATCC Deposit No.Z.
21
CA 02441840 2003-09-22
WO 02/095010 PCT/US02/09785
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CA 02441840 2003-09-22
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CA 02441840 2003-09-22
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CA 02441840 2003-09-22
WO 02/095010 PCT/US02/09785
Description of Table 1B.1 and Table 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 117
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 ID:",
for cDNA clones related to each contig sequence disclosed in Table 1A andlor
1B. The third column
of Tables 1B.1 and 1B.2 provide unique contig identifiers, "Contig >D:" for
each of the contig
sequences disclosed in these tables. The fourth column of Tables 1B.1 and 1B.2
provide the sequence
identifiers, "SEQ ID NO:X", for each of the contig sequences disclosed in
Table 1A and/or 1B.
Table 1B.1
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; 181-186 (1988)); specifically, the
Genetics Computer
Group (GCG) implementation of this algorithm, embodied in the program
PEPT)DESTRUCTURE
(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, OMIM'~'. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins
University
(Baltimore, MD) and National Center for Biotechnology Information, National
Library of Medicine
64
CA 02441840 2003-09-22
WO 02/095010 PCT/US02/09785
(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 OMIM reference identification numbers is provided
in Table 5. Table 5
is a key to the OMIM reference identification numbers (column 1), and provides
a description of the
associated disease in Column 2.
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 )D NO:X) was identified in the corresponding tissue/cell source.
Those tissue/cell source
identifier codes in 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 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.
CA 02441840 2003-09-22
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,--i .-r N ,-, ,~
~ h
o
-o
xx n~t~MMriNNN~
W
r.; OW O ~ N M o0
~ N h O O~
_'~
O N ~ N N N ~
M N N N N
~:
pN~O
~ wi ~ ~ ri M
m N N N
~ N O h t~ h v~
~-i ~O ~t DO O
.~
_
~MM ~~N
h
NNO~N
,
,-
N
ra
x ~
M cn cn N N
N
d
.--i ,.~ M v0 \O
,-i N Ov O O Ov
,~ O~
N ~O v0 M ,~ v~
v0 00 ~ O o0 ~
O~ "'' N N N N
N N N N ~
M
x~~ ~
..-i ~ Wt cn cn cn
,-i cn N N
,-i
~n o0 N O t~
~ -~ O s0 vi
-~
N N h O o0 ~O
M N ~t -~
~ N N ~ M N O
N N N N
O
O
O
~p M
N
M V7
d'
M O
00 O
h
00 V7
M M
M
M
227
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Table 1C summarizes additional polynucleotides encompassed by the invention
(including cDNA
clones related to the sequences (Clone )D:), contig sequences (contig
identifier (Contig ID:)
contig nucleotide sequence identifiers (SEQ ID NO:X)), and genomic sequences
(SEQ )D NO:B).
S The first column provides a unique clone identifier, "Clone ll~:", 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
)D:" 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
1D 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).
Table 1C
cDNA CloneSEQ ID CONTIG BAC ID: SEQ ID EXON
ID NO:X ID: A NO:B From-To
HAUAI83 33 639009 AC010422 1037 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 33 639009 AC018761 1038 1-326
1176-1284
1552-2084
2162-2261
2300-2426
228
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4485-5868
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 33 639009 AC010422 1039 1-315
2004-2289
2650-2741
3554-3830
HAUAI83 33 639009 AC010422 1040 1-202
938-1047
1219-1395
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 33 639009 AC018761 1041 1-202
938-1047
1219-1395
229
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1758-1956
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 33 639009 AC018761 1042 1-82
128-293
1178-1447
1986-2278
2457-2711
3543-3844
HBINS58 37 1352386 AL096774 1043 1-1023
2010-2239
2581-2962
3153-3223
3324-3493
3973-4126
HB1NS58 37 1352386 AL096774 1044 1-341
HBINS58 37 1352386 AL096774 1045 1-142
HCE3G69 43 728432 AC068946 1046 1-108
1186-1324
1746-1835
2138-2284
2448-2545
2718-2861
3091-5889
HCE3G69 43 728432 AC068946 1047 1-191
HCE3G69 43 728432 AC068946 1048 1-686
HCEFB80 45 1143407 AL022327 1049 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 51 1016919 AL122003 1050 1-236
531-696
230
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787-817
863-4508
5158-5744
6949-7029
HCNDR47 51 1016919 AL122003 1051 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
HCWGU37 59 1042325 AC007459 1052 1-242
HCWGU37 59 1042325 AC022435 1053 1-218
5587-5754
HCWGU37 59 1042325 AC022051 1054 1-294
HCWGU37 59 1042325 AC023672 1055 1-196
HCWGU37 59 1042325 ACO11101 1056 1-100
HCWGU37 59 1042325 AC034243 1057 1-312
2334-2364
HCWGU37 59 1042325 AC010454 1058 1-218
5588-5755
HCWGU37 59 1042325 AC026144 1059 1-183
HCWGU37 59 1042325 AC009691 1060 1-292
HCWGU37 59 1042325 AL354696 1061 1-181
HCWGU37 59 1042325 AC073219 1062 1-123
HCWGU37 59 1042325 AC027414 1063 1-270
HCWGU37 59 1042325 AC010454 1064 1-303
HDPGTO1 71 771583 AC020978 1065 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
HDPGTO1 71 771583 AC020978 1066 1-384
HDPSB 18 79 1043263 AL355512 1067 1-2572
3049-3871
HDPSB 18 79 1043263 AC006176 1068 1-2571
3048-3872
HDPSB 18 79 1043263 AL355512 1069 1-280
231
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HDPWN93 85 992925 AC004590 1070 1-276
489-591
866-988
1106-1281
1323-1444
1632-1799
1866-2016
2109-2313
2634-3205
3360-3472
3528-3744
3820-5006
6580-6919
7076-7276
8057-8153
8318-8680
HDPWN93 85 992925 AC021491 1071 1-275
488-590
865-987
1105-1280
1322-1443
1631-1798
1865-2015
2108-2312
2633-3204
3359-3471
3527-3743
3819-5005
6579-6918
7075-7275
8054-8150
8315-8677
HI~PWN93 85 992925 AC004590 1072 1-303
727-1252
5721-5846
HDPWN93 85 992925 AC021491 1073 1-303
727-1253
5723-5848
HDPXY01 86 879048 AL354000 1074 1-1319
4848-4975
5229-5600
6561-6654
HI~PXY01 86 879048 AL035362 1075 1-1316
4844-4971
5225-5596
6557-6650
HDPXY01 86 879048 AL354000 1076 1-460
HDPXY01 86 879048 AL354000 1077 1-400
HDPXY01 86 879048 AL035362 1078 1-400
HDPXY01 86 879048 AL035362 1079 1-460
HFVGE32 118 854545 AL160269 1080 1-1122
HFVGE32 118 854545 AL138754 1081 1-1120
HHGCG53 133 340818 AC024037 1082 1-518
HHGCM76 134 662329 AC003665 1083 1-70
232
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304-609
900-1090
1240-1835
2272-2490
2581-3598
HHGCM76 134 662329 AC003665 1084 1-580
851-995
1224-1296
1314-1663
1930-1975
2724-2905
2968-3098
3283-3328
5121-5230
5331-5689
HJACG30 143 895505 AC018512 1085 1-776
HJACG30 143 895505 AC022305 1086 1-878
HJACG30 143 895505 AC002518 1087 1-150
HLTIP94 180 1087335 AC007431 1088 1-1299
HLTIP94 180 1087335 AC007431 1089 1-330
HMSDL37 199 973996 AC012086 1090 1-3328
HMSDL37 199 973996 AC018811 1091 1-3051
HMSDL37 199 973996 AC018494 1092 1-3029
HMSDL37 199 973996 AC012086 1093 1-224
HMSDL37 199 973996 AC012086 1094 1-468
HMSDL37 199 973996 AC018811 1095 1-222
HMSDL37 199 973996 AC018811 1096 1-468
HMSDL37 199 973996 AC018494 1097 1-224
HMSDL37 199 973996 AC018494 1098 1-1854
HNGBC07 217 1037631 AL022339 1099 1-1583
HNGOI12 225 1041375 AC003675 1100 1-2128
HNGOI12 225 1041375 AC001228 1101 1-2129
HNGOI12 225 1041375 AC013791 1102 1-2132
HNHFM14 230 664507 AC020552 1103 1-290
HNHFM14 230 664507 AC020552 ll04 1-96
HPICB53 258 1042309 AC002351 1105 1-82
959-2236
HPICB53 258 1042309 AC020997 1106 1-1329
HPICB53 258 1042309 AC002351 1107 1-115
HPICB53 258 1042309 AC020997 1108 1-201
1064-1126
1665-2153
2308-3502
HPJBK12 260 1011467 AC022033 1109 1-2649
HPJBK12 260 1011467 AC013541 1110 1-2649
HPJBK12 260 1011467 AC022033 1111 1-190
HPJBK12 260 1011467 AC013541 1112 1-190
HPRAL78 263 1352342 AC007783 1113 1-2334
2508-3084
3578-3890
4198-4294
4376-4623
4712-5349
233
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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
15133-15355
15485-15653
16750-16805
16894-17078
17162-17219
18003-18089
21085-21146
21358-21501
HPRAL78 263 1352342 AC007783 1114 1-308
HPRAL78 263 1352342 AC007783 1115 1-1024
HRGBL78 272 910133 AL359541 1116 1-254
2777-3307
3670-3823
4113-4385
4844-5381
5995-7365
HSAWD74 278 460527 AC004951 1117 1-1651
1740-2593
HSAWD74 278 460527 AC004951 1118 1-149
HSAWD74 278 460527 AC004951 1119 1-5057
5082-8353
8404-8996
HTHBG43 312 919911 AL139257 1120 1-36
130-201
330-753
1823-2214
2331-2440
2728-2834
2920-3028
3370-3514
4153-5236
5877-6744
6813-7124
8441-9280
9527-9953
10394-10536
10945-11362
11763-11843
12653-12953
13970-14183
14223-14726
234
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15929-16299
16328-16751
17791-18093
18095-18712
18754-24628
24879-25426
HTHBG43 312 919911 AL139257 1121 1-286
HTLN19 317 1046341 AC055750 1122 1-964
HTLN19 317 1046341 AC027463 1123 1-964
HTLN 19 317 1046341 AC055750 1124 1-236
HTLN19 317 1046341 AC027463 1125 1-236
HTOIZ02 321 826312 AC023146 1126 1-2101
3106-3722
HTOIZ02 321 826312 AC023146 1127 1-278
HTPCS72 323 854941 AL008639 1128 1-106
1457-1595
1666-2484
2910-3006
3705-4147
4768-5141
5304-5536
5746-5874
7114-7241
7468-7711
7963-8746
9438-12408
12884-14976
HTPCS72 323 854941 AL008639 1129 1-720
HTPIH83 324 919916 AL158821 1130 1-1862
1880-3126
Table 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 cardiovascular disease or
disorder
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 cardiovascular disease or disorder.
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In another embodiment, the present invention also encompasses methods of
detecting,
preventing, diagnosing, prognosticating, treating, and/or ameliorating a
cardiovascular 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 )D NO:Y") indicates the Sequence Listing
SEQ >D
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 (or
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,
confirm, and/or 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
236
CA 02441840 2003-09-22
WO 02/095010 PCT/US02/09785
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).
237
CA 02441840 2003-09-22
WO 02/095010 PCT/US02/09785
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238
CA 02441840 2003-09-22
WO 02/095010 PCT/US02/09785
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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 8
CONTENANT LES PAGES 1 A 242
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brevets
JUMBO APPLICATIONS/PATENTS
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THIS IS VOLUME 1 OF 8
CONTAINING PAGES 1 TO 242
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