Research Project
2189454
The vast majority of studies on prostanoid metabolism have focused on prostaglandin E2, prostacyclin, thromboxane A2, and the leukotrienes, which are collectively involved in the regulation of a wide range physiological and pathophysiological events. Although it has been the subject of less intense investigation, it has been reported that prostaglandin D2 (PGD2) prevents platelet aggregation, elevates protein synthesis in liver tissue, and induces systematic mastocytosis. In the brain, PGD2 has been reported to regulate sleep, lower body temperature and modulate secretion of luteinizing hormone. PGD2 has also been reported to have cytotoxic, anti-tumoral and anti-metastatic properties. Two forms of PGD2 synthase have been reported: a "spleen-form" which synthesizes PGD2 in several tissues including spleen, platelets, liver, stomach, small intestine and colon; and a second form which appears restricted to the brain. The goal of this proposal is to develop molecular probes to detect PGD2 synthase proteins and mRNAs, and procedures for commercial production of active PGD2 synthase enzymes. Availability of these products will facilitate basic, clinical and pharmaceutical research on the regulation of PGD2 synthase gene expression, development of novel therapeutic agents, as well as for the treatment of systemic mastocytosis, sleep disorder, hypothermia and convulsion. PROPOSED COMMERCIAL APPLICATION: Purified prostaglandin D2 synthase and molecular probes (antibodies and cDNA) will initially be marketed for research and pharmaceutical development. This enzyme can be used to screen for specific activators and inhibitors of the spleen form of PGD2 synthase, and for its localization and genetic regulation. In the long term these products are anticipated to have applications for diagnosis and therapeutic intervention in sleep disorders, hypothermia, convulsion, systemic mastocytosis and cancer.
