Transcriptional Regulation of PGHS-1 in megakaryocytes

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): The goal of the proposed research is to understand the transcriptional regulation of PGHS-1 during megakaryocytopoiesis. PGHS-1 catalyzes the committed step in the synthesis of thromboxane A2, a potent mediator of platelet aggregation. Platelet PGHS-1 is a major pharmacological target for prevention and treatment of cardiovascular diseases. However, very little is known about the regulation of PGHS-1 gene expression. Promoter reporter assays suggest that distal control elements are important for inducible PGHS-1 gene expression in a megakaryocytic cell line. Further examination of PGHS-1 gene regulation will be approached in several megakaryocytic cell lines induced to differentiate with phorbol ester or primary cytokines. The specific aims are: 1) to identify cis- and trans-elements involved in regulating PGHS-1 gene transcription using a combination of in vitro assays; 2) to characterize the importance of cis regulatory elements through functional and in vivo analysis; and 3) to determine if identified regulatory cis-elements and flanking gene sequence are necessary for full inducible expression of a transgenic PGHS-1 construct in a megakaryocytic cell line. Novel information of PGHS-1 gene regulation will further our understanding of the biochemical differences between PGHS-1 and its isoform PGHS-2. These studies may lead to more effective therapeutic targeting in the areas of thrombosis and other diseases in which PGHS-1 has been implicated.