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:
- 金额:$ 9.49万
- 依托单位:
- 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:
- 关键词:AddressAgingAnimal ModelAnimalsAppointmentAstrocytesBiochemistryBiogenesisBiological AssayBrainCaenorhabditis elegansChemical ExposureChemicalsDataDiseaseDissectionEndoplasmic ReticulumEnvironmental ExposureExerciseExposure toFacultyGastrointestinal tract structureGeneticGoalsHealthHealth BenefitHumanHydroxydopaminesInstitutionInterventionK-Series Research Career ProgramsKnowledgeLinkLiteratureLiverMeasuresMediatingMitochondriaMitochondrial ProteinsModelingMolecularNematodaNerve DegenerationNeurodegenerative DisordersNeuronsNeurotoxinsOrganismParkinson DiseasePathway interactionsPatient-Focused OutcomesPhysical ExercisePhysiologicalProcessProteinsRecommendationReportingResearchResistanceRisk AssessmentRodentRoleRotenoneSwimmingTestingTherapeutic InterventionTissuesToxic effectToxicant exposureToxicologyTranslatingWorkage relatedcareerconditioningdopaminergic neuronendoplasmic reticulum stressexercise regimenhuman tissueimprovedin vivoinsightmitochondrial dysfunctionmutantneuroprotectionneurotrophic factornew therapeutic targetoverexpressionreproductiveresponsetargeted treatmenttoxicant
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.
项目摘要
运动显著改善了人类健康的多个方面,但其分子机制
运动对健康的益处还没有得到很好的理解。运动的已知全身益处包括
大量的神经保护;例如,体育锻炼是改善患者的唯一干预措施。
帕金森氏病的治疗方法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蛋白介导的,
叫做神经营养因子。例如,最近的研究报道中脑星形胶质细胞增加-
运动后的衍生性神经营养因子(MANF)水平。MANF通常储存在内质网中,
内质网(ER),并在ER应激条件下释放。MANF特异性保护多巴胺能
神经元,但MANF的保护机制,以及运动在这一过程中的具体作用,
并没有得到很好的理解。有趣的是,MANF与线粒体蛋白相互作用,
和活动增加运动,提高了MANF介导运动诱导的
线粒体稳健性。了解细胞和生物体范围内的机制,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至关重要
评估神经毒性。
这个独立之路职业发展奖将实验性地测试以下两者之间的关系:
运动、神经营养因子MANF和化学毒物诱导的神经退行性变
多功能模式生物秀丽隐杆线虫。这个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,
游泳运动在C。秀丽线虫同时改善线粒体健康并增加MANF
表情我假设运动条件反射通过防止
化学应激诱导的内质网应激和线粒体功能障碍,这种保护作用是
通过神经营养因子MANF介导。为了验证这一假设,我将野生型,MANF-
缺乏和MANF过表达的线虫对运动调节和/或神经毒素(鱼藤酮和
6-羟基多巴胺)暴露。然后,我将确定MANF状态对毒物反应的影响,
评估ER应激,线粒体功能障碍,和神经退行性病变的三个MANF遗传
通过以下目标的背景: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在雌激素受体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;目标3。确定运动和MANF对毒物诱导的神经变性的影响。
总的来说,从这项研究中获得的知识将建立一个长期机制解剖的模型,
锻炼对有毒物质暴露和衰老疾病都有好处。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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
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- 批准号:
10496067 - 财政年份:2023
- 资助金额:
$ 9.49万 - 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:
$ 9.49万 - 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:
$ 9.49万 - 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:
$ 9.49万 - 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:
$ 9.49万 - 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:
10513823 - 财政年份:2020
- 资助金额:
$ 9.49万 - 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:
$ 9.49万 - 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:
$ 9.49万 - 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:
$ 9.49万 - 项目类别:
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