Exercise, MANF, and chemical-induced neurodegeneration

运动、MANF 和化学物质引起的神经变性

基本信息

批准号：
10020404
负责人：
Jessica Helene Hartman
金额：
$ 9.49万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-19 至 2020-11-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10020404
关键词：
Address Aging Animal Model Animals Appointment Astrocytes Biochemistry Biogenesis Biological Assay Brain Caenorhabditis elegans Chemical Exposure Chemicals Data Disease Dissection Endoplasmic Reticulum Environmental Exposure Exercise Exposure to Faculty Gastrointestinal tract structure Genetic Goals Health Health Benefit Human Hydroxydopamines Institution Intervention K-Series Research Career Programs Knowledge Link Literature Liver Measures Mediating Mitochondria Mitochondrial Proteins Modeling Molecular Nematoda Nerve Degeneration Neurodegenerative Disorders Neurons Neurotoxins Organism Parkinson Disease Pathway interactions Patient-Focused Outcomes Physical Exercise Physiological Process Proteins Recommendation Reporting Research Resistance Risk Assessment Rodent Role Rotenone Swimming Testing Therapeutic Intervention Tissues Toxic effect Toxicant exposure Toxicology Translating Work age related career conditioning dopaminergic neuron endoplasmic reticulum stress exercise regimen human tissue improved in vivo insight mitochondrial dysfunction mutant neuroprotection neurotrophic factor new therapeutic target overexpression reproductive response targeted treatment toxicant

项目摘要

Project Summary Exercise dramatically improves multiple facets of human health, but the molecular mechanisms by which exercise confers health benefits are not well understood. Known systemic benefits from exercise include substantial neuroprotection; for example, physical exercise is the sole intervention that improves patient outcomes and slows progression of Parkinson’s Disease. The mechanism for neuronal improvement is unclear, but an intriguing possibility is that protection is mediated through modulation of secreted proteins called neurotrophic factors. For example, recent studies have reported increased mesencephalic astrocyte- derived neurotrophic factor (MANF) levels after exercise. MANF is normally stored in the endoplasmic reticulum (ER), and is released upon conditions of ER stress. MANF specifically protects dopaminergic neurons, but the mechanisms by which MANF is protective, and the specific role of exercise in this process, are not well understood. Interestingly, MANF interacts with mitochondrial proteins, and mitochondrial content and activity are increased by exercise, raising the possibility that MANF mediates exercise-induced mitochondrial robustness. Understanding cellular and organism-wide mechanisms operating to confer benefits from exercise is essential for informing exercise recommendations for neurodegenerative disease and risk assessment for neurotoxicants. This Pathway to Independence career development award will experimentally test the relationship between physical exercise, the neurotrophic factor MANF, and chemical toxicant-induced neurodegeneration in the versatile model organism Caenorhabditis elegans. This model is especially appropriate for this question because MANF is the only neurotrophic factor conserved in nematodes, and my preliminary data shows swimming exercise in C. elegans concomitantly improves mitochondrial health and increases MANF expression. I hypothesize that exercise conditioning decreases neurodegeneration by protecting from chemical exposure-induced ER stress and mitochondrial dysfunction, and that this protection is mediated through the neurotrophic factor MANF. To test this hypothesis, I will subject wild-type, MANF- deficient, and MANF-overexpressing nematodes to exercise conditioning and/or neurotoxicant (rotenone and 6-hydroxydopamine) exposures. I will then determine the impact of MANF status on toxicant response by assessing ER stress, mitochondrial dysfunction, and neurodegeneration in the three MANF genetic backgrounds via the following aims: Aim 1. Assess role of MANF in exercise-induced physiological changes; Aim 2. Identify role of MANF in systemic crosstalk between ER stress and mitochondrial dysfunction after toxicant exposure; Aim 3. Determine impact of exercise and MANF on toxicant-induced neurodegeneration. Overall, knowledge gained from this study will establish a model for long-term mechanistic dissection of exercise benefits in the context of both toxicant exposure and diseases of aging.

项目概要运动极大地改善了人类健康的多个方面，但运动的分子机制运动带来的健康益处尚未得到充分了解。运动带来的全身益处包括。实质性的神经保护；例如，体育锻炼是改善患者状况的唯一干预措施；神经系统改善的机制是：尚不清楚，但一个有趣的可能性是保护是通过调节分泌蛋白来介导的例如，最近的研究报告了中脑星形胶质细胞的增加。运动后衍生的神经营养因子 (MANF) 水平通常储存在内质中。网状结构 (ER)，并在 ER 应激条件下释放 MANF，专门保护多巴胺能。神经元，但 MANF 的保护机制，以及运动在此过程中的具体作用，目前尚不清楚，MANF 与线粒体蛋白和线粒体内容物相互作用。和活动通过运动而增加，增加了MANF介导运动诱发的可能性线粒体的稳健性。了解细胞和生物体范围内的机制以带来益处。运动对于了解神经退行性疾病和风险的运动建议至关重要神经毒物评估。该“独立之路”职业发展奖将通过实验检验两者之间的关系体育锻炼、神经营养因子 MANF 和化学毒物引起的神经变性多功能模型生物秀丽隐杆线虫该模型特别适合这个问题。因为MANF是线虫中唯一保守的神经营养因子，我的初步数据显示线虫游泳运动同时改善线粒体健康并增加 MANF 我认为运动调节可以通过防止神经变性来减少神经变性。化学暴露引起的内质网应激和线粒体功能障碍，并且这种保护是通过神经营养因子 MANF 介导为了检验这个假设，我将测试野生型 MANF-。缺乏和MANF过度表达的线虫以进行运动调节和/或神经毒剂（鱼藤酮和然后我将通过以下方式确定 MANF 状态对毒性反应的影响。评估三种 MANF 遗传中的 ER 应激、线粒体功能障碍和神经变性通过以下目标了解背景：目标 1. 评估 MANF 在运动引起的生理变化中的作用；目标 2. 确定 MANF 在 ER 应激和线粒体功能障碍之间的系统串扰中的作用毒物暴露；目标 3. 确定运动和 MANF 对毒物引起的神经变性的影响。总的来说，从这项研究中获得的知识将建立一个长期机械解剖的模型运动对于有毒物质暴露和衰老疾病都有好处。