MOLECULAR PHARMACOLOGY OF LYSOPHOSPHATIDIC ACID

University Of Virginia Charlottesville, Charlottesville VA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Adapted from the Applicant's Abstract): Three years ago the investigators proposed an integrated program of synthetic chemistry and molecular biology with the twin goals of gaining a deeper understanding of the structure activity relationships (SAR) in lysophoshatidic acid (LPA) and related lipid phosphoric acid mediators (LPAMs), and the molecular cloning of a LPA receptor DNA. The investigators have achieved these goals, and they propose now to expand on this success by using recombinant LPA signaling proteins as well as analytical and synthetic chemistry to continue to explore the molecular pharmacology of this intriguing class of lipid mediators. The present aims of the project are stated succinctly as: (1) Developing further the SAR of LPAMs, whereby the pharmacophore systems responsible for agonist and antagonist activities of LPAM receptors will be identified; (2) Targeting additional SAR efforts to identify selective inhibitors of the recently identified LPAM phosphatases, PAP2a and PAP2b; (3) Developing mass spectroscopy methods to identify and quantify known and postulated LPAM species in biologic specimens and (4) Using their novel LPAM receptor to develop a radioligand binding assay, search for related receptor DNAs and dissect LPA signaling pathways. The investigators cite the strength of their program as the combination of synthetic chemistry and molecular pharmacology, an interaction made stronger by their identification of a LPA receptor DNA and the availability of cloned lipid phosphatidate phosphatases. They expect that, at a minimum, their efforts will significantly extend SAR for both the receptor and phosphatases and result in the development of an analytical method for the accurate detection and quantification of LPAMs in biologic specimens. Optimally, they will also develop selective phosphatase inhibitors, identify receptor antagonists and discover novel LPAMs as well as additional receptor subtypes. The results of the proposed studies will lift LPAM chemistry and biology to a higher level of understanding and will provide a firm indication as to whether signaling by this autacoid class is a candidate for therapeutic intervention to influence the course of human disease.