POLY RIBOSE SYNTHETASE &ENDOTHELIAL DYSFUNCTION IN IDDM

Inotek Pharmaceuticals Corporation, Beverly MA

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Abstract

DESCRIPTION (adapted from the applicant's abstract): In a variety of cell types (including vascular endothelial cells and vascular smooth muscle cells), exposure to cytotoxic oxidants such as peroxynitrite, results in cellular energetic failure. Upon DNA strand breakage, the nuclear enzyme poly (ADP) ribose synthetase (PARS) initiates an energy consuming, inefficient repair cycle, with transfer of the ADP ribosyl moiety of NAD to protein acceptors. The resultant depletion of dinucleotide pools is implicated in the process of cell death. In animal and cell culture models, a protective effect of PARS inhibition or lack of PARS gene has been demonstrated. Thus, the investigators propose to define the role of PARS in the process of development of endothelial injury in an in vitro model of diabetes-associated hyperglycemia. Two specific aims are proposed: (1) to establish whether inhibition or genetic inactivation of PARS affects the development of endothelial dysfunction induced by high glucose conditions; and (2) to investigate the mechanism of high glucose-induced endothelial cell death and the role of PARS in the process.