Identification of epigenetic marks underlying exercise-induced neuroprotection in Parkinson’s disease

帕金森病运动诱导神经保护的表观遗传标记的鉴定

• 批准号: 10528178
• 负责人: Alison Bernstein
• 金额: $ 44.38万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528178
• 关键词: 3-Dimensional; Acute; Adult; Aerobic; Aerobic Exercise; Affect; Age-Years; Animal Model; Animals; Automobile Driving; Base Pairing; Biological; Bradykinesia; Candidate Disease Gene; Cell physiology; Characteristics; Chromatin Structure; Clinical Research; Custom; Cytosine; DNA Methylation; DNA Modification Process; DNA Sequence; Data; Diagnosis; Disease; Disease Progression; Disease model; Enteric Nervous System; Environment; Epidemiology; Epigenetic Process; Equilibrium; Event; Exercise; Functional disorder; Gait abnormality; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genomic Segment; Goals; Heritability; Housing; Human; Intervention; Knowledge; Lasers; Life; Light; Linear Regressions; Longevity; Maintenance; Maps; Measures; Mediating; Mediator of activation protein; Methods; Microscopy; Midbrain structure; Modeling; Modification; Monitor; Mus; Nerve Degeneration; Neurons; Neurotoxins; Operative Surgical Procedures; Oxidative Stress; Parkinson Disease; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Population; Predisposition; Proteins; Regimen; Research; Risk; Running; Sequencing By Hybridizations; Substantia nigra structure; Testing; Therapeutic; Time; Tremor; Work; dopaminergic neuron; epidemiology study; epigenome; exhaust; experimental study; gene network; genome-wide; histone modification; laser capture microdissection; motor deficit; motor symptom; mouse genome; mouse model; nervous system disorder; neuron loss; neuroprotection; novel; pars compacta; phenomenological models; pre-clinical; preclinical study; prevent; response; sedentary; sex; symptom treatment; symptomatology; toxicant

Abstract This application seeks to map the DNA modification landscape of the mouse genome in response to levels of exercise that are neuroprotective in a toxicant model of Parkinson’s disease (PD). PD is a debilitating neurological disorder that strikes approximately 1-2% of the adult population greater than 50 years of age. Although we have a number of symptomatic treatments for PD, little can be done to prevent its onset or even slow its progression. However, over the past few years, both preclinical and clinical studies have shown that voluntary exercise may offer these benefits. For example, epidemiological studies indicate that aerobic levels of exercise early in life reduce the risk of developing Parkinson's disease (PD) and delay the progression of PD motor symptoms in already diagnosed patients. These epidemiological findings have been replicated in a number of animal studies that demonstrate exercise-induced neuroprotection against the neurotoxicant MPTP. In addition, only a few studies have explored the cellular mechanisms that underlie this protection, focusing their efforts on specific proteins or genes. While there is value to a target-driven approach, exercise modifies many different cellular processes that likely work together in biological networks. As such, defining genome-wide changes in gene regulation will provide a more complete picture of the biological networks underlying exercise-induced neuroprotection. Here, we propose several experiments to determine whether genome-wide changes in DNA modification occur in response to neuroprotective levels of voluntary exercise as well as whether exercise-induced changes in DNA modifications are stable over time, even as exercise- induced neuroprotection is exhausted (a time to be empirically determined). These unanswered questions will be examined in two aims. In SA1, we will use a combination of laser capture microdissection (LCM) and enzymatic methyl-sequencing to map genome-wide DNA modifications of C57BL/6J mice that perform 3 months of aerobic exercise, a duration which is necessary to induce neuroprotection. Using the proposed methods, we will identify exercise-related changes in DNA modifications at both single base pairs and genomic regions in a population of enriched substantia nigra dopaminergic neurons. In SA2, we will 1) identify if and/or when the neuroprotective effects of voluntary exercise are extinguished, and use this information to, 2) identify which exercise-associated changes in DNA modifications persist across time after exercise cessation. We will use targeted capture hybridization sequencing to determine if exercise- associated changes in DNA methylation of SNpc DA neurons isolated by LCM are maintained or reversed after extinguishment of exercise. Completion of these aims will provide a list of candidate genes that are critical for the maintenance of exercise-induced SNpc neuroprotection, thereby providing novel targets for disease modifying therapies.

抽象的 该应用程序旨在绘制小鼠基因组的DNA修饰局势，以响应于 在帕金森氏病（PD）有毒模型中具有神经保护作用的运动。 PD令人衰弱 大约50岁以上的成年人口的神经疾病大约有1-2％的成年人口。 尽管我们对PD有多种症状治疗，但几乎没有采取任何措施来防止其发作甚至 减慢其进展。但是，在过去的几年中，临床前和临床研究都表明 自愿运动可能会带来这些好处。例如，流行病学研究表明有氧水平 生命早期运动的运动，从而降低了患帕金森氏病（PD）的风险并延迟 已经诊断出患者的PD运动症状。这些流行病学发现已在A中复制 动物研究的数量表明对神经毒性进行运动引起的神经保护作用 MPTP。此外，只有少数研究探索了这种保护的基础的细胞机制， 将他们的精力集中在特定的蛋白质或基因上。虽然目标驱动的方法有价值，但锻炼 修改许多可能在生物网络中共同起作用的不同细胞过程。因此，定义 全基因组调节的全基因组变化将为生物网络提供更完整的图像 潜在的运动引起的神经保护。在这里，我们提出了几个实验，以确定是否 DNA修饰的全基因组变化是响应自愿运动的神经保护水平而发生的 以及运动诱导的DNA修饰变化是否随着时间的推移是否稳定，即使 诱导的神经保护是耗尽的（凭经验确定的时间）。这些未解决的问题 将以两个目标进行检查。在SA1中，我们将使用激光捕获显微解剖（LCM）和 酶甲基序列以绘制执行3的C57BL/6J小鼠的全基因组DNA修饰 几个月的有氧运动，这是诱导神经保护作用所必需的持续时间。使用建议的 方法，我们将确定在单基对和 富集质体的基因组区域尼格拉多巴胺能神经元。在SA2中，我们将1） 确定自愿运动的神经保护作用是否熄灭，并使用此效果 信息向2）确定在随后的时间内持续存在哪些运动相关的DNA修饰变化 运动停止。我们将使用有针对性的捕获杂交测序来确定是否运动 - 通过LCM分离的SNPC DA神经元的DNA甲基化的相关变化被维持或逆转 扑灭运动后。这些目标的完成将提供一份候选基因的清单 维持运动引起的SNPC神经保护至关重要，从而为 疾病修饰疗法。