Conserved Aging Mechanisms Impacting Dopamine Neuron Survival

影响多巴胺神经元存活的保守衰老机制

基本信息

批准号：
10351123
负责人：
Ian Martin
金额：
$ 23.1万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-04 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10351123
关键词：
Affect Affinity Chromatography Age Aging Animal Model Attenuated Brain Cell Aging Cells Cellular Stress Cessation of life Collection DNA Damage Disease model Dopamine Down-Regulation Drosophila genus Environmental Risk Factor Exhibits Exposure to Future Genes Genetic Genetic Variation Goals Health Human Hypoxia LRRK2 gene Link Longevity Measures Mediator of activation protein Messenger RNA Metabolic Metabolic dysfunction Mitochondria Molecular Monitor Nerve Degeneration Nervous system structure Neurites Neurodegenerative Disorders Neurons Neurotoxins Orthologous Gene Other Genetics Oxidation-Reduction Oxidative Stress PARK7 gene PINK1 gene Parkin Parkinson Disease Pathway interactions Pesticides Play Population Predisposition Production Prothrombin Reactive Oxygen Species Regulation Reporter Resistance Ribosomes Risk Factors Role Serotonin Signal Pathway Signal Transduction Sirolimus Stress Substantia nigra structure Tissues Translating Up-Regulation Whole Organism age effect age related aged alpha synuclein biological adaptation to stress dopaminergic neuron early onset endoplasmic reticulum stress experience fly genome wide association study hypoxia inducible factor 1 loss of function mortality mutant neuron loss oxidative damage paralogous gene response stressor

项目摘要

PROJECT SUMMARY The single biggest risk factor for developing Parkinson’s disease is age, suggesting that age-related changes in the brain predispose to loss of dopamine (DA) neuron health and viability. Cell stressors such as oxidative stress and metabolic dysfunction increase with age in many species including humans, and DA neurons are particularly vulnerable to oxidative stress because of their high metabolic demands and intrinsic reactive oxygen species production. Despite a growing body of evidence linking elevated oxidative stress to aging and DA neuron degeneration, the role of oxidative stress-responsive signaling pathways in connecting this stress to enhanced DA neuron vulnerability with age are not well understood. Prior studies link activation of the HIF-1 (hypoxia-inducible factor-1) pathway to suppression of TOR (target of rapamycin) signaling and recent GWAS studies raise the possibility that the interaction of these pathways may be important in regulating lifespan, possibly in response to cellular stress signals. Key components of HIF-1/TOR signaling are also altered in human Parkinson’s disease substantia nigra DA neurons. The primary goal of this proposal is to determine whether age-related oxidative stress results in sustained upregulation of specific signaling mediators in the HIF-1/TOR signaling pathway that promote susceptibility of DA neurons to age- related death and limit organismal lifespan. Studies from multiple animal models including Drosophila indicate that TOR deregulation is a feature of nervous system aging and neurodegenerative disease. We will leverage the natural genetic variation in a collection of Drosophila genetic backgrounds that we find influences reactive oxygen species production, lifespan and DA neuron viability to achieve two primary goals: First, we will examine the effects of aging on brain expression of oxidative stress signaling mediators both in the whole brain as well as in specific vulnerable (i.e. DA) and spared neuronal populations. Second, we will determine the role of these signaling mediators on age-related DA neuron death and lifespan. These exploratory studies will pave the way for detailed characterization of how aging and age-related stress drives upstream regulators of this signaling pathway, and inform broader studies on the role of these signaling mediators in Parkinson’s disease neurodegeneration linked to additional genetic and environmental factors.

项目概要患帕金森病的最大单一危险因素是年龄，这表明与年龄相关的大脑的变化容易导致多巴胺 (DA) 神经元健康和活力的丧失。在许多物种中，氧化应激和代谢功能障碍等随着年龄的增长而增加，包括人类和 DA 神经元特别容易受到氧化应激，因为它们的高尽管身体不断增长，但代谢需求和内在活性氧的产生。有证据表明氧化应激升高与衰老和 DA 神经元变性有关，氧化应激的作用压力响应信号通路将压力与增强的 DA 神经元脆弱性联系起来之前的研究还不清楚 HIF-1（缺氧诱导因子 1）的激活与年龄的关系。 TOR（雷帕霉素靶标）信号传导抑制途径和最近的 GWAS 研究提出了这些途径的相互作用可能对调节寿命很重要，可能在对细胞应激信号的反应也发生了改变。人类帕金森病黑质 DA 神经元该提案的主要目标是确定年龄相关的氧化应激是否导致特定信号持续上调 HIF-1/TOR 信号通路中的介质可促进 DA 神经元对衰老的敏感性包括果蝇在内的多种动物模型的研究。表明 TOR 失调是神经系统衰老和神经退行性疾病的一个特征。我们将利用一系列果蝇遗传背景中的自然遗传变异，我们发现影响活性氧产生、寿命和 DA 神经元活力以实现两个主要目标：首先，我们将研究衰老对大脑氧化应激表达的影响整个大脑以及特定弱势群体（即 DA）中的信号传导介质均未受影响其次，我们将确定这些信号传导介质对年龄相关的作用。这些探索性研究将为详细的 DA 神经元死亡和寿命铺平道路。表征衰老和与年龄相关的压力如何驱动该信号的上游调节器途径，并为有关这些信号传导介质在帕金森病中的作用的更广泛的研究提供信息神经退行性疾病与其他遗传和环境因素有关。