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Bax, Caspases, and Oxidative Stress in the Aging Brain

Bax、半胱天冬酶和衰老大脑中的氧化应激

基本信息

批准号：
9127052
负责人：
JAMES Lee FRANKLIN
金额：
$ 7.5万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9127052
关键词：
Age Aging Aging-Related Process Alzheimer&apos s Disease Animals Antioxidants Apoptosis Apoptotic BCL2 gene Bax protein Binding Sites Biochemical Biological Biological Assay Brain Cardiovascular system Caspase Cell Culture Techniques Cells Cessation of life Chemicals Complex Cytoplasm Cytoplasmic Granules Data Dyes Electron Transport Electrons Equilibrium Excision Goals Health Heart Diseases Induction of Apoptosis Injury Knockout Mice Laboratories Lead Mediating Mediator of activation protein Metabolism Mitochondria Molecular Mus Nervous system structure Neurodegenerative Disorders Neurons Organ Organism Oxidation-Reduction Oxidative Stress Parkinson Disease Pathology Process Production Protein Family Publishing Reactive Oxygen Species Regulation Reporting Research Respiratory Chain Role Site Staining method Stains Stress Stroke Tissues age related aged aging brain base body system cell type cytochrome c inhibitor/antagonist member neuron apoptosis neuropathology normal aging novel prevent pro-apoptotic protein research study respiratory therapy development

项目摘要

DESCRIPTION (provided by applicant): Biological organisms produce a number of reactive oxygen species and other reactive chemical species (RS). Oxidative stress induced by RS contributes to injury in stroke, heart disease, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Most RS are produced by mitochondria as a byproduct of metabolism. Mitochondria-produced RS are removed from cells by antioxidant mechanisms. Excess production or decreased removal can lead to oxidative stress. A considerable amount is known about regulation of mechanisms for removing RS. Much less is known about regulation of RS production by mitochondria. The purpose of this application is to investigate a novel mechanism for regulating production of mitochondrial RS in neurons. The findings from the proposed experiments may aid in understanding oxidative stress in many other tissues as well. Our lab studies mechanisms underlying RS production and clearance in the nervous system and the role of RS in neuronal apoptosis and neurodegenerative diseases. Our preliminary and published data show that both healthy and apoptotic neurons with higher concentrations of the pro-apoptotic protein Bax have higher RS levels than do neurons with lower Bax concentrations and that Bax deletion prevents oxidative stress in the aging mouse brain and other organs. Our overall objective in this project is to understand the role of Bax and other molecular components of apoptosis in generating oxidative stress in the nervous system. Based on our preliminary and published data as well as that of others, we hypothesize that Bax has pro-oxidant effects in both apoptotic and non- apoptotic neurons primarily via a Bax-enabled caspase cleavage of components of the mitochondrial respiratory chain. Such cleavage can lead to increased RS production by augmenting leaking of electrons from the chain. Specific aim 1 will determine the mechanisms by which Bax contributes to RS production in cortical neurons in cell culture. We will concentrate on a role for caspase-mediated damage to mitochondrial respiratory complexes. Specific aim 2 will determine which cell types in the aging mouse brain are subject to Bax-induced oxidative stress and determine how Bax and caspases contribute to this stress. The outlined experiments will further our long-term goals of understanding mechanisms underlying RS-induced damage in the nervous system and of identifying ways to lessen this damage in neuro- and other pathologies.

描述（由申请人提供）：生物有机体产生大量活性氧和其他活性化学物质（RS）。RS诱导的氧化应激导致中风、心脏病和神经退行性疾病（如阿尔茨海默病和帕金森病）的损伤。大多数RS是由线粒体作为代谢的副产品产生的。线粒体产生的RS通过抗氧化机制从细胞中去除。过量的产生或减少的去除可能会导致氧化应激。相当多的是已知的关于消除RS的机制的调节。关于线粒体对RS产生的调节知之甚少。本申请的目的是研究调节神经元中线粒体RS产生的新机制。从拟议的实验结果可能有助于了解氧化应激在许多其他组织以及。我们的实验室研究RS在神经系统中产生和清除的机制以及RS在神经元凋亡和神经退行性疾病中的作用。我们的初步和已发表的数据表明，健康和凋亡的神经元与促凋亡蛋白Bax浓度较高，有较高的RS水平比Bax浓度较低的神经元和Bax缺失防止氧化应激老化小鼠大脑和其他器官。我们在这个项目中的总体目标是了解Bax和细胞凋亡的其他分子组分在神经系统中产生氧化应激中的作用。基于我们的初步和已发表的数据以及其他人的数据，我们假设Bax在凋亡和非凋亡神经元中具有促氧化作用，主要通过线粒体呼吸链组分的caspase激活的半胱天冬酶裂解。这种裂解可以通过增加电子从链中的泄漏而导致RS产生增加。具体目标1将确定Bax在细胞培养中促进皮质神经元RS产生的机制。我们将集中讨论半胱天冬酶介导的线粒体呼吸复合体损伤的作用。具体目标2将确定衰老小鼠大脑中的哪些细胞类型会受到神经元诱导的氧化应激，并确定Bax和半胱天冬酶如何促成这种应激。概述的实验将进一步我们的长期目标，了解RS引起的神经系统损伤的机制，并确定减少神经和其他病理损伤的方法。