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

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.
项目总结

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
An unbiased, automated platform for scoring dopaminergic neurodegeneration in C. elegans.
  • DOI:
    10.1371/journal.pone.0281797
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Clark, Andrew S.;Kalmanson, Zachary;Morton, Katherine;Hartman, Jessica;Meyer, Joel;San-Miguel, Adriana
  • 通讯作者:
    San-Miguel, Adriana
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Jessica Helene Hartman其他文献

Jessica Helene Hartman的其他文献

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{{ truncateString('Jessica Helene Hartman', 18)}}的其他基金

Subcellular-targeted CYP2E1 and alcohol in the brain
大脑中亚细胞靶向 CYP2E1 和酒精
  • 批准号:
    10496067
  • 财政年份:
    2023
  • 资助金额:
    $ 24.9万
  • 项目类别:
Regulation and Consequences of Cytochrome P450 2E1
细胞色素 P450 2E1 的调节和后果
  • 批准号:
    10713697
  • 财政年份:
    2023
  • 资助金额:
    $ 24.9万
  • 项目类别:
Exercise, MANF, and Chemical-Induced Neurodegeneration
运动、MANF 和化学物质引起的神经变性
  • 批准号:
    10380263
  • 财政年份:
    2021
  • 资助金额:
    $ 24.9万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 24.9万
  • 项目类别:
Exercise, MANF, and Chemical-Induced Neurodegeneration
运动、MANF 和化学物质引起的神经变性
  • 批准号:
    10513154
  • 财政年份:
    2020
  • 资助金额:
    $ 24.9万
  • 项目类别:
Exercise, MANF, and Chemical-Induced Neurodegeneration
运动、MANF 和化学物质引起的神经变性
  • 批准号:
    10217454
  • 财政年份:
    2020
  • 资助金额:
    $ 24.9万
  • 项目类别:
Exercise, MANF, and chemical-induced neurodegeneration
运动、MANF 和化学物质引起的神经变性
  • 批准号:
    10020404
  • 财政年份:
    2019
  • 资助金额:
    $ 24.9万
  • 项目类别:
Role of Mitochondrial CYP2E1 in Chemical Exposure-Driven Neurodegeneration
线粒体 CYP2E1 在化学品暴露驱动的神经变性中的作用
  • 批准号:
    9189444
  • 财政年份:
    2016
  • 资助金额:
    $ 24.9万
  • 项目类别:
Role of Mitochondrial CYP2E1 in Chemical Exposure-Driven Neurodegeneration
线粒体 CYP2E1 在化学品暴露驱动的神经变性中的作用
  • 批准号:
    9319548
  • 财政年份:
    2016
  • 资助金额:
    $ 24.9万
  • 项目类别:

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