Secreted factors

Details Secreted factors Secreted factors

2001-03-14

2004-10-05

Martinell, James (Department: 1631)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

C435S006120, C435S252300, C435S325000, C435S320100, C536S023100, C536S023500, C536S024310

Reexamination Certificate

active

06800455

ABSTRACT:

FIELD OF THE INVENTION
The present invention concerns secreted factors encoded by genes differentially regulated in certain diseased tissues. More particularly, the invention concerns nucleic acid encoding novel secreted polypeptide factors, the encoded polypeptides, and compositions containing and methods and means for producing them. The invention further concerns methods based on the use of such nucleic acids and/or polypeptides in the diagnosis and treatment of various diseases, in particular cardiac, renal, or inflammatory diseases.
BACKGROUND OF THE INVENTION
Gene expression patterns, including changes in gene expression between normal and diseased tissues or tissues in various stages of disease progression provide valuable insight into the molecular determinants of normal and abnormal cellular physiology. Accordingly, genes that are differentially expressed in subjects suffering from a disease, such as cardiac, renal or inflammatory disease, relative to normal subjects, are useful targets for intervention to diagnose, prevent or treat such diseases.
Techniques have been developed to efficiently analyze the level of expression of specific genes in cells and tissues. Procedures that can be used to identify and clone differentially expressed genes include, for example, subtractive hybridization (Jiang and Fisher,
Mol. Cell. Different.
1:285-299 [1993]; Jiang etal.,
Oncogene
10, 1855-1864 [1995]; Sagerstrom et al.,
Annu. Rev. Biochem.
66: 751-783 [1997]); differential RNA display (DDRT-PCR) (Watson et al.,
Developmental Neuroscience
15:77-86 [1993]; Liang and Pardee,
Science
257:967-971 [1992]); RNA fingerprinting by arbitrarily primed PCR (RAP-PCR) (Ralph et al.,
Proc. Natl. Acad. Sci. USA
90:10710-10714 [1993]; McClelland and Welsh,
PCR Methods and Applications
4:S66-81 [1994]); representational difference analysis (RDA) (Hubank and Schatz,
Nucl. Acids Res.
22:5640-5648 [1994]); serial analysis of gene expression (SAGE) (Velculescu et al.,
Science
270:484-487 [1995]; Zhang et al.,
Science
276:1268-1272 [1997]); electronic subtraction (Wan et al.,
Nature Biotechnology
4:1685-1691 [1996]); combinatorial gene matrix analyses (Schena et al.,
Science
270:467-470 [1995]), and various modifications and improvements of these and similar techniques.
A particularly attractive method for assessing gene expression is the DNA microarray technique. In this method, nucleotide sequences of interest are plated, or arrayed, on a porous or non-porous substrate that can be paper, nylon or other type of membrane, filter, chip, glass slide or any other suitable solid support. The arrayed sequences are then hybridized with specific DNA probes from cells or tissues of interest. Microarrays of biological materials have been described in a number of patents and patent applications, including, for example, U.S. Pat. Nos. 5,744,305; 5,800,992; 5,807,522; 5,716,785; and European Patent No. 0 373 203.
The DNA microarray technique can be used to monitor the expression level of large numbers of genes simultaneously (to produce a transcript image), and to identify genetic variants, mutations and polymorphisms. This information may be used to determine gene function, understanding the genetic basis of disease, diagnosing disease, and developing and monitoring the activities of therapeutic agents.
An important application of the microarray method allows for the assessment of differential gene expression in pairs of mRNA samples from two different tissues, or in the same tissue comparing normal versus disease states or time progression of the disease. Microarray analysis allows one to analyze the expression of known genes of interest, or to discover novel genes expressed differentially in tissues of interest. Thus, an attractive application of this technology is as a fundamental discovery tool to identify new genes, and their corresponding expression products, which contribute to the pathogenesis of disease and related conditions.
Microarray technology has been successfully applied to large-scale analysis of human gene expression to identify cancer-specific genes and inflammatory-specific genes (DeRisi et al.,
Nat. Genet.,
14(4):457-60 [1996]; Heller et al.,
Proc. Natl. Acad. Sci. USA,
94(6):2150-55 [1997]). DeRisi et al. examined a pre-selected set of 870 different genes for their expression in a melanoma cell line and a non-tumorigenic version of the same cell line. The microarray analysis revealed a decrease in expression for 15/870 (1.7%) and an increase in expression for 63/870 (7.3%) of the genes in non-tumorigenic relative to tumorigenic cells (differential expression values <0.52 or >2.4 were deemed significant). Heller et al. employed microarrays to evaluate the expression of 1000 genes in cells taken from normal and inflamed human tissues. The results indicated that altered expression was evident in genes encoding inflammatory mediators such as IL-3, and a tissue metalloprotease. These results illustrate the utility of applying microarray technology to complex human diseases.
It would be beneficial to discover differentially expressed genes that are related to diseases or various disease states. It would further be beneficial to develop methods and compositions for the diagnostic evaluation and prognosis of conditions involving such diseases, for the identification of subjects exhibiting a predisposition to such conditions, for modulating the effect of these differentially expressed genes and their expression products, for monitoring patients undergoing clinical evaluation for the prevention and treatment of a disease, specifically cardiac, kidney or inflammatory disease, and for monitoring the efficacy of compounds used in clinical trials.
Secreted proteins mediate key biological processes including cell to cell interactions as well as important cellular functions such as cell growth and differentiation, and most protein-based drugs are secreted proteins including insulin, growth hormone, interferons, tissue plasminogen activator ( tPA), and erythropoietin (EPO). It would, therefore, be particularly desirable to identify novel differentially expressed genes encoding secreted proteins.
SUMMARY OF TIE INVENTION
In one aspect, the present invention concerns an isolated nucleic acid molecule comprising a poly- or oligonucleotide selected from the group consisting of:
(a) a polynucleotide encoding a polypeptide having at least about 80% sequence identity with amino acids selected from the group consisting of: 1 to 1203 of SEQ ID NO: 2, amino acids 1 to 193 of SEQ ID NO: 4, amino acids 1 to 236 of SEQ ID NO:6, amino acids 1 to 61 of SEQ ID NO: 8, amino acids 1 to 79 of SEQ ID NO:10, amino acids 1 to 92 of SEQ ID NO:12, amino acids 1 to 86 of SEQ ID NO:14, amino acids 1 to 36 of SEQ ID NO:16, amino acids 1 to 83 of SEQ ID NO:18, amino acids 1 to 82 of SEQ ID NO:20, amino acids 1 to 462 of SEQ ID NO:22, amino acids 1 to 170 of SEQ ID NO:24, amino acids −26 to 233 of
FIG. 13
(amino acids 1 to 259 of SEQ ID NO:26), amino acids 1 to 30 of SEQ ID NO:28, amino acids 1 to 39 of SEQ ID NO:30, amino acids 1 to 541 of SEQ ID NO: 33, amino acids 1 to 30 of SEQ ID NO:35, amino acids 1 to 100 of SEQ ID NO:37, amino acids 1 to 65 of SEQ ID NO:39, amino acids 1 to 42 of SEQ ID NO:41, amino acids 1 to 46 of SEQ ID NO:43, amino acids 1 to 313 of SEQ ID NO:46, amino acids 1 to 58 of SEQ ID NO:51, amino acids −35 to 387 of
FIG. 29
(amino acids 1 to 422 of SEQ ID NO:53), amino acids 1 to 58 of SEQ ID NO:55, amino acids 1 to 52 of SEQ ID NO:57, amino acids 1 to 245 of SEQ ID NO:59, amino acids 1 to 142 of SEQ ID NO:63, amino acids 1 to 49 of SEQ ID NO:67, amino acids 1 to 70 of SEQ ID NO:69, amino acids 1 to 113 of SEQ ID NO: 72, and amino acids 1 to 114 of SEQ ID NO:74, and amino acids 1 to 97 of SEQ ID NO:76; or a transmembrane domain (membrane spanning segment/region) deleted or inactivated variant thereof;
(b) a polynucleotide encod

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