Exercise, MANF, and Chemical-Induced Neurodegeneration

运动、MANF 和化学物质引起的神经变性

• 批准号: 10307629
• 负责人: Jessica Helene Hartman
• 金额: $ 24.9万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-24 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307629
• 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; 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; Oxidopamine; 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

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.

项目摘要 运动大大改善了人类健康的多个方面，但分子机制 锻炼承认健康益处的理解尚未得到充分理解。锻炼的已知系统性好处包括 实质性神经保护；例如，体育锻炼是改善患者的唯一干预措施 结果和减慢了帕金森氏病的进展。神经元改善的机制是 不清楚，但有趣的可能性是通过调节分泌蛋白来介导保护 称为神经营养因素。例如，最近的研究报道了Messencephalic Astrocyte- 运动后衍生的神经营养因子（MANF）水平。 MANF通常存储在内质中 网状（ER），并在ER应力条件下释放。 MANF专门保护多巴胺能 神经元，但受到MANF保护的机制，以及锻炼在此过程中的具体作用， 有趣的是，MANF与线粒体蛋白和线粒体含量相互作用 通过锻炼增加活动，增加了MANF介导锻炼引起的可能性 线粒体鲁棒性。了解为会议福利运行的细胞和生物范围的机制 运动对于为神经退行性疾病和风险的锻炼建议提供信息至关重要 评估神经毒性。 这项通往独立职业发展奖的途径将在实验上测试 体育锻炼，神经营养因子MANF和化学有毒物质诱导的神经退行性 多功能模型有机体秀丽隐杆线虫。该模型特别适合这个问题 因为MANF是在线虫中保守的唯一神经营养因素，而我的初步数据显示 秀丽隐杆线虫中的游泳运动伴随着改善线粒体健康并增加了manf 表达。我假设锻炼条件通过保护神经退行性因素而下降 化学暴露引起的ER应力和线粒体功能障碍，并且这种保护是 通过神经营养因子MANF介导。为了检验这一假设，我将进行野生型，manf- 不足和过表达MANF的线虫对运动调节和/或神经毒性（鱼藤酮和/或 6-羟基多巴胺）暴露。然后，我将通过 评估三个MANF通用的ER应力，线粒体功能障碍和神经变性 背景通过以下目的：目标1。评估MANF在运动引起的身体变化中的作用； AIM 2。确定MANF在ER应力和线粒体功能障碍之间的全身串扰中的作用 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。 总体而言，这项研究获得的知识将建立一个模型，用于长期机理解剖 在毒物暴露和衰老疾病的背景下，运动益处。