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

• 批准号: 8953564
• 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
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8953564
• 关键词: Age; Aging; Aging-Related Process; Alzheimer' 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; 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; public health relevance; research study; respiratory; therapy development

 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）：生物有机体产生许多活性氧和其他活性化学物质（RS）。 RS 引起的氧化应激会导致中风、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。生产过多或清除减少会导致氧化应激。关于去除 RS 的机制的调节已有相当多的了解。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。拟议实验的结果也可能有助于了解许多其他组织中的氧化应激。 我们的实验室研究神经系统中 RS 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，具有较高浓度促凋亡蛋白 Bax 的健康和凋亡神经元比具有较低 Bax 浓度的神经元具有更高的 RS 水平，并且 Bax 缺失可以防止衰老小鼠大脑和其他器官的氧化应激。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成分在神经系统中产生氧化应激中的作用。根据我们以及其他人的初步和已发表的数据，我们假设 Bax 主要通过 Bax 启用的 caspase 裂解线粒体呼吸链的成分，对凋亡和非凋亡神经元具有促氧化作用。这种裂解会增加链中电子的泄漏，从而导致 RS 产量增加。具体目标 1 将确定 Bax 促进细胞培养中皮质神经元 RS 产生的机制。我们将集中研究半胱天冬酶介导的线粒体呼吸复合物损伤的作用。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 Bax 诱导的氧化应激的影响，并确定 Bax 和半胱天冬酶如何导致这种应激。概述的实验将进一步促进我们的长期目标，即了解 RS 引起的神经系统损伤的机制，并确定减轻神经和其他病理损伤的方法。