PARG- Mediated Cell Death: Biochemical Mechanisms

PARG-介导的细胞死亡：生化机制

• 批准号: 7068509
• 负责人: WEIHAI YING
• 金额: $ 8.06万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-20 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7068509
• 关键词: DNA damage; NAD nucleosidase; apoptosis; astrocytes; brain injury; cell death; enzyme activity; enzyme inhibitors; glycosides; laboratory mouse; mitochondria; necrosis; neurons; neuroprotectants; oxidative stress; pentosyltransferase; statistics /biometry; stroke; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Stroke is one of the leading causes of death and disability in the U.S. New information regarding the mechanisms of ischemic neuronal death and new treatment strategies for stroke is urgently needed. Previous studies have indicated a key role of excessive poly (ADP-ribose) polymerase-1 (PARP-1) activation in oxidative cell death in cerebral ischemia and several other debilitating diseases. Recent studies by us and other laboratories have provided direct evidence demonstrating that PARP-1 induces cell death by depleting NAD+, which leads to mitochondria permeability transition (MPT) and nuclear translocation of apoptosis inducing factor. We have also provided the first evidence suggesting that poly(ADP-ribose) glycohydrolase (PARG), the sole catabolizing enzyme in poly(ADP-ribose) metabolism, is an important mediator of oxidative and excitotoxic neuronal death. Recent studies have further suggested that PARG and PARP-1 are promising therapeutic targets for decreasing ischemic neuronal death both in vivo and in vitro. However, in contrast to the rapidly growing information regarding PARP-1 in cell death, the mechanisms underlying the roles of PARG in cell death are unclear. The major objective of this study is to investigate the mechanisms underlying the PARG inhibition-produced neuroprotection. The information from this study may provide fundamental information regarding the downstream events mediating PARG/PARP-1 cytotoxicity, and suggest new strategies to decrease ischemic brain injury at delayed time points. Specific aim 1 of this study is to test the hypothesis that PARG inhibition can decrease apoptotic changes of neurons and astrocytes induced by oxidative stress and other genotoxic agents by preventing NAD+ depletion; and Specific aim 2 is to test the hypothesis that PARG inhibition can prevent genotoxic agent-induced mitochondrial permeability transition (MPT) of astrocytes.

描述（由申请人提供）：卒中是美国死亡和残疾的主要原因之一。迫切需要有关缺血性神经元死亡机制和卒中新治疗策略的新信息。以往的研究表明，过度的聚（ADP-核糖）聚合酶-1（PARP-1）的激活在脑缺血和其他几种衰弱性疾病中的氧化性细胞死亡中起着关键作用。我们和其他实验室最近的研究提供了直接证据，证明PARP-1通过消耗NAD+，导致线粒体通透性转换（MPT）和凋亡诱导因子的核转位来诱导细胞死亡。我们还提供了第一个证据表明，聚（ADP-核糖）糖水解酶（PARG），在聚（ADP-核糖）代谢的唯一分解代谢酶，是一个重要的介导的氧化和兴奋毒性神经元死亡。最近的研究进一步表明，PARG和PARP-1是在体内和体外减少缺血性神经元死亡的有希望的治疗靶点。然而，与关于PARP-1在细胞死亡中的快速增长的信息相反，PARG在细胞死亡中的作用的潜在机制尚不清楚。本研究的主要目的是研究PARG抑制产生神经保护作用的机制。这项研究的信息可能提供有关下游事件介导的PARG/PARP-1细胞毒性的基本信息，并提出新的策略，以减少缺血性脑损伤在延迟的时间点。本研究的具体目的1是检验PARG抑制可通过防止NAD+耗竭来减少氧化应激和其他遗传毒性剂诱导的神经元和星形胶质细胞凋亡变化的假设;具体目的2是检验PARG抑制可防止遗传毒性剂诱导的星形胶质细胞线粒体通透性转换（MPT）的假设。