BIOCHEMICAL MECHANISMS OF NEURONAL DEATH

神经元死亡的生化机制

• 批准号: 6140087
• 负责人: WEIHAI YING
• 金额: $ 3.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6140087
• 关键词: adenine phosphoribosyltransferase; cell death; cerebral ischemia /hypoxia; confocal scanning microscopy; gene induction /repression; genetic regulatory element; genetically modified animals; laboratory mouse; membrane proteins; mitochondrial membrane; neurons; neuroprotectants; neurotoxins; nicotinamide adenine dinucleotide; pentosyltransferase; tissue /cell culture

A fast growing body of evidence suggests that poly(ADP-ribose) polymerase (PARP) activation plays an important role in ischemic brain damage. However, the mechanisms underlying PARP neurotoxicity remain unstudied. Based on the evidence suggesting the possible effects of a PARP-produced NAD+ decrease on mitochondria permeability transition (MPT) and oxidative stress, experiments are designed in this proposal to test the hypothesis that PARP stimulation elicits neuronal death by potentiating MPT and oxidative damage. Primary murine neuronal mono- cultures are used as in vitro models. Both PARP inhibitors and PARP gene disruption are used to depress PARP activation. This study may suggest novel mechanisms of excitotoxic and oxidative neuronal death, and provide new insights for attenuating ischemic brain damage.

越来越多的证据表明，聚（ADP-核糖）聚合酶（PARP）的激活在缺血性脑损伤中起着重要作用。 然而，PARP神经毒性的潜在机制尚未研究。基于表明PARP产生的NAD+降低对线粒体通透性转换（MPT）和氧化应激的可能影响的证据，在该提议中设计了实验来检验PARP刺激通过增强MPT和氧化损伤来诱发神经元死亡的假设。原代鼠神经元单培养物用作体外模型。PARP抑制剂和PARP基因破坏均用于抑制PARP活化。本研究可能提示兴奋性毒性和氧化性神经元死亡的新机制，并为减轻缺血性脑损伤提供新的见解。