POLY RIBOSE SYNTHETASE & ENDOTHELIAL DYSFUNCTION IN IDDM

描述(改编自申请人的摘要)：多种细胞类型 (包括血管内皮细胞和血管平滑肌细胞)， 暴露于细胞毒性氧化剂，如过氧亚硝酸盐，导致细胞 精力旺盛的失败。在DNA链断裂时，核酶聚(ADP) 核糖合成酶(PARS)启动一种耗能、低效的修复 循环，将NAD的ADP核糖基部分转移到蛋白质受体。这个 由此产生的二核苷酸池的耗尽与细胞的过程有关 死亡。在动物和细胞培养模型中，PARs的保护作用 PARS基因的抑制或缺失已被证实。因此，调查人员 建议明确PARs在内皮细胞发育过程中的作用 糖尿病相关高血糖体外模型的损伤。两个具体的 提出的目标是：(1)确定抑制或基因失活 PARS对高脂诱导的血管内皮细胞功能障碍的影响 (2)探讨高血糖的发生机制。 葡萄糖诱导内皮细胞死亡及PARS在此过程中的作用。

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.