Determining the role of OXR1 in aging and Alzheimer's disease

确定 OXR1 在衰老和阿尔茨海默病中的作用

• 批准号: 10461321
• 负责人: Lisa M Ellerby
• 金额: $ 85.14万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461321
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-42; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Animal Model; Apolipoprotein E; Atrophic; Autophagocytosis; Autopsy; Binding Proteins; Cell Death; Collaborations; Data; Diet; Disease; Electrophysiology (science); Elements; Etiology; Genes; Genetic; Goals; Homeostasis; Human; Impaired cognition; Intervention; Late Onset Alzheimer Disease; Letters; Link; Longevity; Lysosomes; Measures; Mediating; Medicine; Membrane; Methods; Modeling; Molecular; Mustard; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nutrient; Oxidative Regulation; Oxidative Stress; PLA2G6 gene; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Play; Prosencephalon; Proteins; Proteomics; Public Health; Regulation; Research; Resistance; Risk Factors; Role; Seizures; Signal Pathway; Testing; Therapeutic; Therapeutic Intervention; Tissues; Up-Regulation; Variant; Work; age related; age related neurodegeneration; base; cholinergic; design; dietary restriction; epidemiology study; fly; genetic risk factor; genome wide association study; healthspan; induced pluripotent stem cell; knock-down; loss of function; mouse model; neuroprotection; novel; overexpression; prevent; programs; promoter; protective effect; proteostasis; stem cell model; tau Proteins; therapeutic development; therapeutic target; tool; trans-Golgi Network; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-42; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Animal Model; Apolipoprotein E; Atrophic; Autophagocytosis; Autopsy; Binding Proteins; Cell Death; Collaborations; Data; Diet; Disease; Electrophysiology (science); Elements; Etiology; Genes; Genetic; Goals; Homeostasis; Human; Impaired cognition; Intervention; Late Onset Alzheimer Disease; Letters; Link; Longevity; Lysosomes; Measures; Mediating; Medicine; Membrane; Methods; Modeling; Molecular; Mustard; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nutrient; Oxidative Regulation; Oxidative Stress; PLA2G6 gene; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Play; Prosencephalon; Proteins; Proteomics; Public Health; Regulation; Research; Resistance; Risk Factors; Role; Seizures; Signal Pathway; Testing; Therapeutic; Therapeutic Intervention; Tissues; Up-Regulation; Variant; Work; age related; age related neurodegeneration; base; cholinergic; design; dietary restriction; epidemiology study; fly; genetic risk factor; genome wide association study; healthspan; induced pluripotent stem cell; knock-down; loss of function; mouse model; neuroprotection; novel; overexpression; prevent; programs; promoter; protective effect; proteostasis; stem cell model; tau Proteins; therapeutic development; therapeutic target; tool; trans-Golgi Network

PROJECT SUMMARY/ABSTRACT Despite identifying some of the genetic risk factors for AD, the precise etiology of most cases of Late-Onset Alzheimer's disease (LOAD) is unknown. Subsequently, therapies to treat AD have been largely unsuccessful. Two important risk factors for AD, aging, and diet, with aging being the greatest risk factor for AD, remain largely ignored. Dietary restriction (DR), one of the most robust interventions to slow aging, also delays the onset of Alzheimer’s disease (AD) in multiple models across species. We exploited the short lifespan and powerful genetic tools in D. melanogaster to identify that mustard (mtd)/oxidative stress resistance protein 1 (OXR1) in neurons is required for the protective effects of DR on lifespan. Importantly, we have observed that OXR1 protects against age-related neurodegeneration in fly and human-induced pluripotent stem cell (iPSC) derived models of neurodegenerative diseases. The mechanisms by which OXR1 protects against neurodegeneration remains unclear. We observed that inhibiting OXR1 reduces retromer proteins while enhancing retromer function, rescues the deleterious effects of inhibiting OXR1. Furthermore, we found that alterations in OXR1 and several retromer proteins are associated with an increased risk of AD in humans using proteomics data from over 1000 AD patients from the Accelerating Medicines Program-Alzheimer’s Disease (AMP-AD) network. Here, we propose to test the hypothesis that OXR1 enhances retromer function to slow aging and neurodegeneration using fly and human iPSC models of AD. In the first aim, we will determine the mechanisms of regulation of OXR1 and how that influences aging and age-related neuronal damage. In the second aim, we will determine the DR-dependent role of OXR1 in enhancing retromer function and the role of retromer in mediating the protective effects of DR. To determine the mechanism by which OXR1 enhances retromer function upon DR; we will use proteomics to determine and characterize the protein binding partners of OXR1. In the third aim, we will test the role of OXR1 in protecting against neurodegeneration in models of AD, and by enhancing retromer function. We will test whether OXR1 modulates AD pathology in fly models that overexpress human tau or amyloid β (Aβ). We will overexpress OXR1 and retromer proteins in forebrain cholinergic and cortical neuron derived AD iPSCs and measure AD endpoints: Aβ42/40 accumulation, cell death, and electrophysiology. Because OXR1 regulates retromer function in the fly, we will evaluate whether this regulation is conserved in human AD-derived iPSCs and carry out omics approaches to identify key signaling pathways mediating OXR1’s protective effects. By characterizing retromer function and protein networks regulated by OXR1 and their role in aging and age-dependent neurodegeneration, we will provide novel targets for developing therapeutics to slow AD-related pathologies and extend healthspan. Furthermore, we will determine whether reuse of proteins through retromer under nutrient limiting conditions is neuroprotective and slows aging.

项目摘要/摘要 尽管确定了AD的某些遗传危险因素，但大多数晚期病例的精确性病因 阿尔茨海默氏病（负载）尚不清楚。随后，治疗AD的疗法在很大程度上没有成功。 广告，衰老和饮食的两个重要危险因素，衰老是广告的最大危险因素，但仍在很大程度上 被忽略。饮食限制（DR）是减慢衰老的最强大干预措施之一，也延迟了 各种各样的多种模型中的阿尔茨海默氏病（AD）。我们利用了短暂的寿命和强大的 D. melanogaster中的遗传工具识别芥末（MTD）/氧化应激抗性蛋白1（OXR1） 在神经元中，DR对生命周期的受保护作用是必需的。重要的是，我们观察到OXR1 预防蝇中与年龄相关的神经变性，并衍生出人类诱导的多能干细胞（IPSC） 神经退行性疾病的模型。 OXR1预防神经变性的机制 仍然不清楚。我们观察到，抑制OXR1会减少还原蛋白，同时增强逆转录器 功能，反应抑制OXR1的有害作用。此外，我们发现OXR1和 使用蛋白质组学数据，几种逆转录蛋白与人类中AD的风险增加有关 来自加速药品计划 - 阿尔茨海默氏病（AMP-AD）网络的1000多名AD患者。这里， 我们建议测试OXR1增强逆转录功能的假设，从而缓慢衰老和神经变性 使用AD的Fly和人IPSC模型。在第一个目标中，我们将确定调节的机制 OXR1及其如何影响衰老和与年龄相关的神经元损伤。在第二个目标中，我们将确定 OXR1在增强逆转录功能和逆转录中的作用中的DR依赖性作用在介导 博士的保护作用。确定OXR1在DR时增强还原功能的机制； 将使用蛋白质组学来确定和表征OXR1的蛋白质结合伴侣。在第三个目标中，我们将 测试OXR1在AD模型中预防神经退行性中的作用，并通过增强逆转录器 功能。我们将测试OXR1是否调节过表达人tau或 淀粉样β（Aβ）。我们将在前脑胆碱能和皮质神经元中过表达OXR1和缩回蛋白 衍生的AD IPSC并测量AD端点：Aβ42/40的积累，细胞死亡和电生理学。 由于OXR1在苍蝇中调节还原器的功能，因此我们将评估该调节是否保守 人类AD衍生的IPSC并采用OMICS方法来识别介导OXR1的关键信号通路 保护作用。通过表征由OXR1调节的逆转功能和蛋白质网络及其在 衰老和年龄依赖性神经变性，我们将为开发治疗以减慢治疗提供新的靶标 与广告相关的病理并扩展健康范围。此外，我们将确定是否重复使用蛋白质 通过养分限制条件下的缩回剂是神经保护性的，并减慢了衰老。