Quark Biotech, Inc.

Quark Pharmaceuticals, Inc.

Paz Einat

Rami Skaliter

Elena Feinstein

Shlomit Gilad

Aviv Regev

Avital Grossman

Fruma Yehiely

Hagar Kalinski

Orna Mor

Orit Segev

Alexander Faerman

Raja C Mugasimangalam

Louis Deiss

Dina Zezin-Sonkin

Lion Novak

Louis Paul Deiss

Elena Efimova

Aviva Samach

Nora Cecilia Vasquez-Iaslop

Sylvie Luria

Levy Ulanovsky

According to the present invention, purified, isolated and cloned nucleic acid polynucleotide encoding hypoxia-regulating genes and the proteins thereof and antibodies directed against the proteins which have sequences as set forth in SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5 and SEQ ID No:6 are provided. The present invention further provides transgenic animals and cell lines as well as knock-out organisms of these sequences. The present invention further provides methods of regulating angiogenesis or apoptosis or regulating response to hypoxic conditions in a patient in need of such treatment. The present invention also provides a method of diagnosing the presence of ischemia in a patient including the steps of analyzing a bodily fluid or tissue sample from the patient for the presence or gene product of at least one expressed gene (up-regulated) as set forth in the group comprising SEQ ID No:2; SEQ ID No:3; SEQ ID No:4; SEQ ID No:5; and SEQ ID No:6 and where ischemia is determined if the up-regulated gene or gene product is ascertained.

Hypoxia-regulated genes

A method for the identification of genes that are essential for the maintenance of specific cell phenotypes is disclosed. The method includes the initial step of identifying a cell type with a phenotype of interest. Gene inactivation is performed on an aliquot of cells of the cell type of interest. Selection is then performed to an aliquot of the cell culture to which gene inactivation has been applied. Cells which continue to maintain the phenotype following gene inactivation have not had the gene of interest inactivated whereas cells in which genes necessary for maintaining the phenotype have been inactivated have been lost. Utilizing subtraction analysis between treated and untreated aliquots the gene in the cells which has been inactivated that affects the phenotype of interest is identified. Genes that are identified by the method are also disclosed as well as antibodies directed against the gene product of the identified genes. Further a customized kit for the practice of the gene identification method is also disclosed.

Therapeutic modulation of the Fas pathway

There are provided polynucleotides that are modulated by hypoxic conditions. The disclosure includes such genes and proteins as well as analogs, salts and functional derivatives of such proteins, and DNA encoding such analogs, and methods of use. Methods for treating the effects of stroke, hypoxia and/or ischemia by regulating such genes or proteins are also disclosed. The presence of hypoxia or a hypoxia-associated pathology may be diagnosed by screening for the presence of at least one polynucleotide having the nucleic acid sequence according to the present invention. Methods of regulating hypoxia associated pathologies are also provided.

Sequences characteristic of hypoxia-regulated gene transcription

The disclosure relates to human and mechanical stress induced genes, in particular gene 608, and functional equivalents, probes therefor, tests to identify such genes, polypeptide expression products of such genes, antibodies to the polypeptides, uses for such genes, expression products and antibodies, e.g., in diagnosis (for instance risk determination), treatment, prevention, or control, of osteoporosis or fractures; and to diagnostic, treatment, prevention, or control methods or processes, as well as compositions therefor and methods or processes for making and using such compositions, and receptors therefor and methods or processes for obtaining and using such receptors.

Genes associated with mechanical stress, expression products therefrom, and uses thereof

There are provided polynucleotides which are modulated by hypoxic conditions. The disclosure includes such genes and proteins as well as analogs, salts and functional derivatives of such proteins, and DNA encoding such analogs, and methods of use. Methods for treating the effects of stroke, hypoxia and/or ischemia by regulating such genes or proteins are also disclosed. The presence of hypoxia or a hypoxia-associated pathology may be diagnosed by screening for the presence of at least one polynucleotide having the nucleic acid sequence according to the present invention. Methods of regulating hypoxia associated pathologies are also provided.

A method for enrichment of natural antisense mRNA which involves hybridization of cDNA obtained from sense RNA with cDNA obtained from antisense RNA, followed by DNA polymerase treatment of the sense-antisense hybrid DNA molecule. A natural antisense library can be generated by cloning of sense-antisense hybrid DNA molecules in a vector.

Method for enrichment of natural antisense messenger RNA

According to the present invention, purified, isolated and cloned nucleic acid polynucleotide encoding hypoxia-regulating genes and the proteins thereof and antibodies directed against the proteins which have sequences as set forth in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 are provided. The present invention further provides transgenic animals and cell lines as well as knock-out organisms of these sequences. The present invention further provides methods of regulating angiogenesis or apoptosis or regulating response to hypoxic conditions in a patient in need of such treatment. The present invention also provides a method of diagnosing the presence of ischemia in a patient including the steps of analyzing a bodily fluid or tissue sample from the patient for the presence or gene product of at least one expressed gene (up-regulated) as set forth in the group comprising SEQ ID NO:2; SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:5; and SEQ ID NO:6 and where ischemia is determined if the up-regulated gene or gene product is ascertained.

Antibody against hypoxia proteins

Neuroleukin (SEQ ID NO:8) has been discovered to be hypoxia regulated. Furthermore, it serves as an astrocyte motility factor. Astrocyte motility can be inhibited by a neuroleukin inhibitor.

This invention provides a method of sorting genes comprising: (1) preparing ds cDNA molecules from mRNA molecules (2) digesting the ds cDNA molecules (3) ligating to the digested cDNA molecules a set of dsDNA oligonucleotide adaptors; (4) amplifying the ligated cDNA molecules; and (5) sorting the amplified cDNA molecules into nonoverlapping groups. This invention also provides two additional methods of sorting genes. This invention further provides a method of making sub-libraries of ligation sets.

Sequence-dependent gene sorting techniques

Isolated hypoxia-regulated polypeptides have sequences as set forth in SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:7 and SEQ ID NO:11. Antibodies directed against such polypeptides may be prepared.

The present invention provides a method of identifying clones encoding for membranal and secreted proteins by deriving probes from membrane-bound polysomes and free-polysomes, and performing a microarray-based comparison of the relative abundance of the different RNA species. Analysis of the results of such comparison and resultant identification of clones encoding for membranal or secreted proteins, provides an efficient tool for identifying targets of drug development. The present invention further provides a method of augmenting a microarray analysis by utilizing RNA extracted from specific subcellular compartments as templates for DNA probes. The method may be used together with conventional differential analysis techniques for improvement of their analysis and gene identification functions.

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Nes Ziona, Israel

Paz Einat