Age Impaired ER Homeostasis in Wake-Active Neurons: BiP/Nox2 Crosstalk

唤醒活跃神经元中年龄受损的内质网稳态：BiP/Nox2 串扰

• 批准号: 7673713
• 负责人: NIRMALA NIRINJINI NAIDOO
• 金额: $ 19.69万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673713
• 关键词: ADP-Ribosylation Factors; Acute; Age; Aging; Alzheimer' s Disease; American; Animals; Apoptotic; Attenuated; Behavior; Behavioral; Brain; Catechols; Cells; Cerebellum; Deterioration; Disease; Elderly; Endoplasmic Reticulum; Ensure; Enzymes; Equilibrium; Event; Failure; Feedback; Functional disorder; GRP78 gene; Genetic Transcription; Hippocampus (Brain); Homeostasis; Hour; Hypoxia; Impairment; Injury; Laboratories; Lead; Link; Longevity; Maintenance; Modeling; Modification; Molecular; Molecular Chaperones; Mus; NADPH Oxidase; Nerve Degeneration; Neurons; Oxidases; Oxidative Stress; Parkinson Disease; Pathway interactions; Phosphorylation; Physiological; Play; Population; Predisposition; Process; Production; Protein Biosynthesis; Proteins; Quality Control; Quality of life; Research Design; Research Personnel; Resistance; Role; Series; Shunt Device; Signal Pathway; Signal Transduction; Sleep; Sleep Deprivation; System; Time; Translational Repression; Translations; Up-Regulation; Wakefulness; Work; age related; aged; attenuation; base; biological adaptation to stress; brain tissue; cognitive function; endoplasmic reticulum stress; functional disability; hippocampal pyramidal neuron; insight; nerve injury; noradrenergic; normal aging; novel therapeutic intervention; overexpression; oxidative damage; polypeptide; protein aggregate; protein aggregation; protein folding; protein misfolding; relating to nervous system; response; scaffold; stressor; tool

DESCRIPTION (provided by applicant): Normal aging results in a relentless deterioration of both sleep and wakefulness. Impairments in both behavioral states become more pronounced in many age-dependent neurodegenerative processes. Impaired wakefulness interferes with cognitive function and quality of life for millions of older Americans. The proposed studies are a collaborative effort between two labs to merge pathways of age-related neural injury that each lab has identified. Dr. Naidoo has recently demonstrated that prolonged wakefulness activates the unfolded protein response in the brain. Young mice maintain protein homeostasis, in part, by increasing BiP and attenuating protein translation. In contrast, aged animals mount an insufficient BiP response and manifest ER dyshomeostasis with increased GADD153/CHOP. Her lab will explore the role BiP plays in age-related declines in ER homeostatic response to prolonged wakefulness using murine models with altered BiP levels globally and in select wake neuronal groups (Aim 1). Dr. Veasey's laboratory has identified neuronal NADPH oxidase as a major contributor to protein damage in a model of oxidative injury. These NADPH oxidase-positive neurons (noradrenergic and dopaminergic) develop age-related impaired ER homeostasis earlier than in non-NADPH oxidase wake neurons. Her group has identified increased endoplasmic reticulum (ER) injury with GADD153/CHOP activation, ribosomal disaggregation and protein aggregation in the NADPH oxidase-positive wake neurons. Having select groups of wake-active neurons with differential age-related injury presents a valuable tool with which to identify mechanisms by which aging impairs wake function. We hypothesize that repeated NADPH oxidase activation in catecholaminergic neurons across the lifetime disrupts ER homeostasis in these neurons sufficiently to result in a progressive accumulation of irreversibly misfolded proteins (Aim 2). The studies are designed to determine why select populations of wake neurons are more susceptible to age-related injury and will link two pathogenic mechanisms implicated in the aging of protein homeostasis to explain differential susceptibility to aging decline in neuronal function. Wake impairments may lead to novel therapeutic approaches to enhance daytime functioning in healthy elderly and those with neurodegenerative processes. The proposed studies examine mechanisms by which aging impairs wakefulness. We hypothesize that an oxidase enzyme in wake neurons progressively disrupts the chaperoning system in the endoplasmic reticulum. Consequently protein homeostasis is compromised and toxic protein aggregates accumulate.

描述（由申请人提供）：正常的衰老导致睡眠和清醒的持续恶化。这两种行为状态的损伤在许多年龄依赖性神经退行性过程中变得更加明显。对数以百万计的美国老年人来说，觉醒能力受损会干扰认知功能和生活质量。拟议的研究是两个实验室之间的合作努力，以合并每个实验室已确定的与年龄相关的神经损伤途径。奈杜博士最近证明，长时间的清醒会激活大脑中未折叠蛋白的反应。幼鼠维持蛋白质稳态，部分是通过增加BiP和减弱蛋白质翻译。相比之下，老龄动物的BiP反应不足，并且随着GADD153/CHOP的增加而表现出内质网失衡。她的实验室将探索BiP在小鼠模型中对长时间清醒的内质网稳态反应的年龄相关下降中所起的作用，该模型在全球和选定的清醒神经元组中改变了BiP水平（目的1）。Veasey博士的实验室已经确定，在氧化损伤模型中，神经元NADPH氧化酶是导致蛋白质损伤的主要因素。这些NADPH氧化酶阳性神经元（去甲肾上腺素能和多巴胺能）比非NADPH氧化酶觉醒神经元更早出现与年龄相关的内质网稳态受损。她的研究小组发现，在NADPH氧化酶阳性的清醒神经元中，GADD153/CHOP激活、核糖体解体和蛋白质聚集增加了内质网（ER）损伤。选择具有不同年龄相关损伤的觉醒活跃神经元组提供了一种有价值的工具，用于识别衰老损害觉醒功能的机制。我们假设儿茶酚胺能神经元中的NADPH氧化酶在一生中反复激活，足以破坏这些神经元中的内质网稳态，从而导致不可逆错误折叠蛋白的进行性积累（目的2）。这些研究旨在确定为什么选定的觉醒神经元群体更容易受到与年龄相关的损伤，并将两种与蛋白质稳态老化有关的致病机制联系起来，以解释神经元功能对衰老衰退的不同易感性。清醒障碍可能会导致新的治疗方法，以增强健康老年人和神经退行性疾病患者的日间功能。提出的研究考察了衰老损害清醒的机制。我们假设觉醒神经元中的氧化酶逐渐破坏内质网中的陪伴系统。因此，蛋白质稳态被破坏，有毒蛋白质聚集。