This program proposes an interdisciplinary effort to broaden our understanding of the roles of mediators such as eicosanoids and nitric oxide in the pathogenesis of cerebrovascular thrombosis and brain injury and to enhance our knowledge on the regulation on the regulation and augmentation of their synthesis. Our major goal is to elucidate the fundamental mechanisms by which important endothelial and neuronal genes are regulated and to bring these basic investigations in clinical applications in improved care of patients with cerebrovascular thrombosis and brain injury. Substantial progresses have been made during the previous and present funding periods. These progresses contribute significantly to the rapid advance in this area of research. In this renewal application, we will pursue ongoing project ongoing projects and add new areas of research. Four projects and two core units are proposed. . Project 1, Regulation of Eicosanoid Biosynthesis, is a continuing project aimed at characterization of the transcriptional regulation of endothelial COX-1 and PGI synthase genes. Project 2, Induction of NOS-3 and COX-2 by Vasoprotective agents, is an extension of project 1.
It aims at elucidating the mechanism by which lysophosphatidylcholine and estrogen induces housekeeping NOS-3 and inducible COX-2 genes. Project 3, Role of Cox-2 in Brain Trauma Pathophysiology, proposes to test the hypothesis that COX-2 induction contributes to traumatic brain injury pathophysiology, and anti- inflammatory agents, methylprednisone and IL-10 attenuates COX-2 expression. Project 4, Structure-Function Relationships of TXA2 and PGI2 Receptors, is an extension of project 2 of the current program. It proposes to use a combination of biochemical, biophysical and molecular genetic techniques to map the ligand binding sites of these two receptors. Core A provides administrative coordination and Core B laboratory support for all projects. Thus, the scope of this program ranges from structural biology, cellular and molecular biology to in vivo animal models and there exists an exciting potential for a rapid application of basic information to clinical management of stroke and brain injury and vice versa. The program involves professional personnel who have a long standing interest in thrombosis and stroke research with diverse but complementary expertises in vascular biology, hematology, neurology, neurobiology, biochemistry, cell-molecular biology, structural biology, enzymology and pharmacology. There is an active interaction among investigators. This program has a tract record for cultivating trainees and young investigators. It is intended that this program will enable several laboratories to work individually and together to achieve the highest degree of innovating and productivity.
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