Ortho-Mcneil Pharmaceutical Corp.

Ortho Pharmaceutical Corporation

Janssen Pharmaceutica Nv

Patricia Andrade-Gordon

Andrew Lawrence Darrow

Jenson Qi

Wai-Ping Leung

Cailin Chen

Jian-Shen Qi

Jenson (Jian-Shen) Qi

William Joel Hoekstra

Raymond W Colburn

Claudia K Derian

Lubing Zhou

Lisa Minor

Bruce P Damiano

Christopher Van Besien

Mary Pat Beavers

Robert Schulingkamp

Jianshen Qi

Michael F Addo

Dennis Stone

Administration of U-II to rats caused an increase in the redness or the skin temperature of the ear of the rats. The increase was inhibited by compounds that decease the biological activity of the U-II/UT receptor. Thus, the present invention provides methods of measuring the biological activity of an U-II receptor by monitoring the redness or the skin temperature of the ear of an animal, and the use of the methods to test compounds for their abilities to increase or decrease the biological activity of an U-II receptor.

Method of measuring the biological activity of an urotensin II receptor

A novel human cDNA, termed PRSS11-L, was isolated which encodes a polypeptide that belongs to the S2/HtrA serine protease family. The PRSS11-L mRNA is widely expressed in several tissues throughout the body by multi-tissue Northern blotting. The full-length PRSS11-L cDNA, was cloned, expressed and purified. Proteolytic activity was demonstrated using the protein substrate casein. The isolated nucleic acid or polypeptide molecule of the invention can be used in detection assays, gene therapy, and screening assays.

Human PRSS11-like S2 serine protease and uses thereof

This invention relates to nucleic acid encoding guinea pig PAR 4 and to the protein encoded thereby. The guinea pig DNA and protein are useful for the development of models of human platelet aggregation. The invention further relates to an animal model to assess the role of PAR antagonists in thrombosis.

Guinea pig proteinase-activated receptor 4 and its activating peptide

A novel human nucleic acid and polypeptide, termed PRSS11-L, are disclosed. PRSS11-L, which is observed in tissues throughout the body, can be used in methods of detection, gene therapy, and screening.

Human PRSS11-Like S2 serine protease and uses thereof

Polypeptides corresponding to a novel S1 serine protease family member, termed protease D-G, and nucleic acids encoding them are described. The materials may be used, for example, in screening assays to identify protease D-G modulators and in methods for diagnosing or treating conditions associated with aberrant protease D-G activity.

Human serine protease D-G polypeptide

Here we describe the molecular identification of a cDNA encoding a novel serine protease we have termed protease EOS. The deduced amino acid sequence, and it alignment with other well-characterized serine proteases indicates that it is a member of the S1 serine protease family. We have found that the protease EOS mRNA is expressed in platelets and leukocytes and more specifically eosinophils. Although this protease is abundantly expressed in ovary, retina and stomach, where it may perform important functions, its expression in platelets and certain cells of the immune system suggests that it may play roles in thrombosis and in the immune process. Enzymatically active protease EOS is amenable to further biochemical analyses for the identification of physiological substrates and specific modulators.

DNA encoding the human serine protease EOS

Here we describe the molecular identification of a cDNA encoding a novel serine protease we have termed protease EOS. The deduced amino acid sequence, and it alignment with other well-characterized serine proteases indicates that it is a member of the S1 serine protease family. We have found that the protease EOS mRNA is expressed in platelets and leukocytes and more specifically eosinophils. Although this protease is abundantly expressed in ovary, retina and stomach, where it may perform important functions, its expression in platelets and certain cells of the immune system suggests that it may play roles in thrombosis and in the immune process. Enzymatically active protease EOS is amenable to further biochemical analyses for the identification of physiological substrates and specific modulators

Methods for Identifying modulators of serine protease EOS

Here we describe the molecular identification of a cDNA encoding a novel serine protease we have termed D-G. The deduced amino acid sequence, and it's alignment with other well characterized serine proteases clearly indicates that it is a member of the S1 serine protease family. We have found that the protease D-G mRNA is widely expressed in several tissues throughout the body including epidermis, fibroblasts, keratinocytes, colon, small intestine, stomach, lung, kidney, bone marrow, lymph node, thymus, ovary, prostate, uterus and spinal cord. Interestingly, this protease contains a hydrophobic stretch of amino acids which is a putative transmembrane near the NH -terminus. Thus, this serine protease is thought to be synthesized as a type II integral protein. We expressed a soluble form of this novel human protease by inserting the portion of the protease D-G cDNA, encoding the catalytic domain, in a zymogen activation construct designed to permit the generic activation of heterologous serine protease catalytic domains. The result is an active preparation of protease D-G that has an activity against a subset of amidolytic substrates. This enzymatically active protease D-G preparation is now amenable to further biochemical analyses for the identification of physiological substrates as well as specific inhibitors.

DNA encoding human serine protease D-G

Antibody immunologically reactive with serine protease EOS

Transgenic mice with a non-functional proteinase activated receptor-2 (PAR2) gene are prepared by targeted disruption of the endogenous PAR2 gene. The resulting transgenic mice display a phenotype including a lack of a hypotensive response to administration of the peptide, SLIGRL, and a reduction in carrageenin-induced paw edema compared to wild type mice.

PAR2 modified transgenic mice

A transgenic animal with alterations in an thrombin receptor gene is prepared by introduction of an altered thrombin receptor gene into a host animal. The resulting transgenic animals do not produce functional thrombin receptor molecules.

Thrombin receptor deficient transgenic mice

Nipecotic acid-derived compounds of formula (I): ##STR1## are disclosed as useful in treating platelet-mediated thrombotic disorders.

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Doylestown, PA, United States of America

Patricia Andrade-Gordon