Neuronal signaling : Oxidants & Alzheimers disease

神经信号传导：氧化剂

基本信息

批准号：
7259359
负责人：
RICHARD S. JOPE
金额：
$ 22.86万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7259359
关键词：
Aftercare Age Alzheimer&apos s Disease Apoptosis Apoptotic Attenuated Binding CREB1 gene Caspase Caspase Inhibitor Categories Cell Cycle Arrest Cell Death Cell Nucleus Cells Cessation of life Condition Cyclic AMP-Responsive DNA-Binding Protein DNA DNA Damage Development Enzymes Family Family member Figs - dietary G-Protein-Coupled Receptors GTP-Binding Proteins GTPase-Activating Proteins Gene Expression Glycogen (Starch) Synthase Glycogen Synthase Kinases Goals Heterotrimeric GTP-Binding Proteins Impairment Lead Link Lipids Measurement Mediating Messenger RNA Molecular Monomeric GTP-Binding Proteins Muscarinic Acetylcholine Receptor Muscarinics Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Nuclear Nuclear Protein Nuclear Proteins Numbers Oxidants Oxidative Stress Parkinson Disease Phosphatidylinositols Phosphorylation Phosphotransferases Prevalence Production Protein p53 Proteins Reactive Oxygen Species Receptor Activation Reporting Role Second Messenger Systems Signal Pathway Signal Transduction Site Stress Stroke System TP53 gene Testing Time base caspase-3 follow-up human RGS2 protein insight loss of function member neuron loss neuronal survival novel novel strategies protective effect receptor receptor coupling response rho transcription factor

项目摘要

DESCRIPTION (provided by applicant): Oxidative stress may be the single most prevalent cause of neuronal dysfunction in neurodegenerative disorders, and its prevalence underscores the need to clarify mechanisms causing and attenuating the deleterious effects, the overall goals of this project. We report exciting and novel results: (1) DNA damaging agents that elevate p53 cause a novel mechanism of activation of the pro-apoptotic glycogen synthase kinase-3b (GSK3b). (2) Oxidative stress induces RGS2 (Regulator of G-protein Signaling 2) expression, a G-protein GTPase-activating protein, providing a mechanistic basis for impaired signaling. (3) Stimulation of muscarinic receptors greatly attenuates oxidative stress-induced apoptosis, remarkably as effectively as a general caspase inhibitor. These results provide important new insights about mechanisms that contribute to oxidative stress-induced impairments and about mechanisms capable of attenuating the deleterious effects. Specific Aim 1 will test the hypothesis that oxidative stress and DNA damage activate p53-mediated signaling encompassing recruitment of GSK3b by a novel activation mechanism. We will test the hypotheses that p53-induced activation of GSK3b leads to inhibition of survival-promoting transcription factor substrates of GSK3b, and promotes responses to p53, identify the p53-binding domain on GSK3b, determine if p53 binding alters the association of GSK3b with other proteins, identify the GSK3b-binding domain on p53 and determine if GSK3b binding alters p53 functions. Specific Aim 2 will test the hypothesis that oxidative stress and DNA damage induce the expression of RGS2 which attenuates muscarinic receptor-coupled signaling and facilitates oxidative stress-induced apoptosis. We will identify the signal mediating H202-induced increases in RGS2, Determine if H202-induced increases in RGS2 impair muscarinic receptor-coupled signaling, and test if IGS2 expression is pro-apoptotic role after oxidative stress. Specific Aim 3 will test the hypothesis that stimulated muscarinic receptors protect cells from oxidative stress, identify the blocked site in -1202-inducedsignaling, test the hypothesis that muscarinic receptors provide protection from other apoptotic conditions, identify the signaling pathways activated by muscarinic receptors providing protection, and test the hypothesis that activation of Rho family small G-proteins is protective.

描述（由申请人提供）：氧化应激可能是神经退行性疾病中神经元功能障碍的最普遍原因，其普遍性强调需要澄清导致和减弱有害影响的机制，这是该项目的总体目标。我们报告了令人兴奋的新颖结果：(1) 升高 p53 的 DNA 损伤剂导致促凋亡糖原合成酶激酶 3b (GSK3b) 的激活的新机制。 (2) 氧化应激诱导 RGS2（G 蛋白信号传导调节器 2）表达，这是一种 G 蛋白 GTP 酶激活蛋白，为信号传导受损提供机制基础。 (3) 刺激毒蕈碱受体可极大地减弱氧化应激诱导的细胞凋亡，其效果与一般的 caspase 抑制剂相当。这些结果提供了关于导致氧化应激引起的损伤的机制以及能够减轻有害影响的机制的重要新见解。具体目标 1 将检验氧化应激和 DNA 损伤激活 p53 介导的信号传导（包括通过一种新的激活机制招募 GSK3b）的假设。我们将测试以下假设：p53 诱导的 GSK3b 激活会抑制 GSK3b 的生存促进转录因子底物，并促进对 p53 的反应，识别 GSK3b 上的 p53 结合结构域，确定 p53 结合是否会改变 GSK3b 与其他蛋白质，识别 p53 上的 GSK3b 结合域并确定 GSK3b 结合是否会改变 p53 功能。具体目标 2 将检验氧化应激和 DNA 损伤诱导 RGS2 表达的假设，RGS2 会减弱毒蕈碱受体偶联信号传导并促进氧化应激诱导的细胞凋亡。我们将鉴定介导 H2O2 诱导的 RGS2 增加的信号，确定 H2O2 诱导的 RGS2 增加是否损害毒蕈碱受体偶联信号传导，并测试 IGS2 表达在氧化应激后是否具有促凋亡作用。具体目标 3 将检验受刺激的毒蕈碱受体可保护细胞免受氧化应激的假设，识别 -1202 诱导信号传导中的阻断位点，检验毒蕈碱受体提供保护免受其他凋亡情况的假设，识别由提供保护的毒蕈碱受体激活的信号传导途径，并检验 Rho 家族小 G 蛋白的激活具有保护作用的假设。