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，其流行率强调了阐明引起和衰减有害影响的机制的必要性，这是该项目的整体目标。我们报告了令人兴奋的新结果：（1）升高p53的DNA破坏药物会引起促凋亡糖原合酶激酶激酶-3B（GSK3B）激活的新型机制。（2）氧化应激诱导RGS2（G蛋白信号传导的调节剂2）表达，一种G蛋白GTPase激活蛋白，为信号受损提供了机械基础。（3）刺激毒蕈碱受体极大地减弱了氧化应激诱导的凋亡，这与一般caspase抑制剂一样有效。这些结果提供了有关有助于氧化应激引起的损害以及能够减弱有害影响的机制的机制的重要新见解。具体目标1将检验以下假设：氧化应激和DNA损伤激活p53介导的信号传导，包括通过一种新型的激活机制募集GSK3B。 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结合改变了p53功能。具体目标2将检验以下假设：氧化应激和DNA损伤会诱导RGS2的表达，从而减弱毒蕈碱受体偶联的信号传导并促进氧化应激诱导的凋亡。我们将确定介导H202诱导的RGS2的增加的信号，确定H202诱导的RGS2的增加是否会损害毒蕈碱受体偶联的信号，并测试IgS2表达在氧化应激后是否促凋亡。具体目标3将检验以下假设：刺激的毒蕈碱受体保护细胞免受氧化应激，确定-1202诱导的信号的阻塞位点，检验毒蕈碱受体提供保护免受其他凋亡条件的保护的假说，确定信号传导途径被毒核如菌受体所激活的信号途径可保护肌液受体，以保护和测试smill thement formess smill grophins smill grotation grotation gropation grotation grotation grotation grote grote gpr gpr g prote。