Exercise, MANF, and chemical-induced neurodegeneration

项目摘要 运动极大地改善了人类健康的多个方面，但其分子机制 运动带来的健康益处还没有被很好地理解。已知的锻炼的系统性好处包括 强大的神经保护；例如，体育锻炼是改善患者状况的唯一干预措施 帕金森氏症的转归和延缓进展。神经元改善的机制是 尚不清楚，但一个有趣的可能性是，保护是通过调节分泌的蛋白质来调节的 称为神经营养因子。例如，最近的研究报告说，中脑星形胶质细胞- 运动后衍生神经营养因子(MANF)水平。MANF通常储存在内质中 内质网(ER)，在内质网应激条件下释放。MANF特异性保护多巴胺能 但MANF的保护机制，以及运动在这一过程中的具体作用， 都没有被很好地理解。有趣的是，MANF与线粒体蛋白相互作用，线粒体含量 和活动通过运动增加，增加了MANF介导运动诱导的可能性 线粒体健壮性。了解细胞和生物体范围内的运作机制以赋予利益 运动对于为神经退行性疾病和风险提供运动建议是必不可少的 对神经毒物的评估。 这一独立职业发展之路奖将在实验中测试 运动、神经营养因子MANF和化学毒物诱导的神经变性 多功能模式生物秀丽线虫。这个模型特别适合于这个问题。 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和增加MANF 表情。我假设，运动条件作用通过保护 化学暴露诱导内质网应激和线粒体功能障碍，这种保护是 通过神经营养因子MANF介导。为了验证这一假设，我将让野生型MANF- 缺乏和过度表达MANF的线虫对运动条件作用和/或神经毒物(鱼藤酮和 6-羟基多巴胺)暴露。然后，我将通过以下方式确定MANF状态对毒物反应的影响 评估三种MANF基因的内质网应激、线粒体功能障碍和神经退行性变 背景通过以下目的：目的1.评估MANF在运动诱导的生理变化中的作用； 目的2.确定MANF在内质网应激和线粒体功能障碍之间的系统性串扰中的作用 毒物暴露；目的3.确定运动和MANF对毒物诱导的神经退行性变的影响。 总体而言，从这项研究中获得的知识将为长期机制解剖建立一个模型 运动在有毒物质暴露和老年病的背景下都有好处。

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.