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
基本信息
- 批准号:10528178
- 负责人:
- 金额:$ 44.38万
- 依托单位:
- 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:2022-06-15 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcuteAdultAerobicAerobic ExerciseAffectAge-YearsAnimal ModelAnimalsAutomobile DrivingBase PairingBiologicalBradykinesiaCandidate Disease GeneCell physiologyCharacteristicsChromatin StructureClinical ResearchCustomCytosineDNA MethylationDNA Modification ProcessDNA SequenceDataDiagnosisDiseaseDisease ProgressionDisease modelEnteric Nervous SystemEnvironmentEpidemiologyEpigenetic ProcessEquilibriumEventExerciseFunctional disorderGait abnormalityGene ExpressionGene Expression RegulationGenesGeneticGenomic SegmentGoalsHeritabilityHousingHumanInterventionKnowledgeLasersLifeLightLinear RegressionsLongevityMaintenanceMapsMeasuresMediatingMediator of activation proteinMethodsMicroscopyMidbrain structureModelingModificationMonitorMusNerve DegenerationNeuronsNeurotoxinsOperative Surgical ProceduresOxidative StressParkinson DiseasePathologyPathway interactionsPatientsPeripheralPharmaceutical PreparationsPopulationPredispositionProteinsRegimenResearchRiskRunningSequencing By HybridizationsSubstantia nigra structureTestingTherapeuticTimeTremorWorkdopaminergic neuronepidemiology studyepigenomeexhaustexperimental studygene networkgenome-widehistone modificationlaser capture microdissectionmotor deficitmotor symptommouse genomemouse modelnervous system disorderneuron lossneuroprotectionnovelpars compactaphenomenological modelspre-clinicalpreclinical studypreventresponsesedentarysexsymptom treatmentsymptomatologytoxicant
项目摘要
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.
摘要
本申请寻求绘制小鼠基因组的DNA修饰景观,以响应小鼠基因组的DNA修饰水平。
在帕金森病(PD)的中毒模型中,运动是神经保护的。PD是一种使人衰弱的
神经系统疾病,约1-2%的50岁以上的成年人患病。
虽然我们有一些对症治疗PD,但几乎不能预防其发作,甚至不能预防其复发。
减缓其进程。然而,在过去的几年里,临床前和临床研究都表明,
自愿锻炼可以提供这些好处。例如,流行病学研究表明,
在生命早期进行锻炼可以降低患帕金森病(PD)的风险,并延缓帕金森病的进展。
已确诊患者的PD运动症状。这些流行病学发现在一个
许多动物研究证明运动诱导的神经保护作用可对抗神经毒物
MPTP。此外,只有少数研究探索了这种保护的细胞机制,
专注于特定的蛋白质或基因。虽然目标驱动的方法有其价值,
改变了许多不同的细胞过程,这些过程可能在生物网络中一起工作。因此,定义
基因调控的全基因组变化将为生物网络提供更完整的图景
潜在的运动诱导的神经保护作用。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发生在对自愿运动的神经保护水平的反应中
以及运动引起的DNA修饰变化是否会随着时间的推移而稳定,即使在运动时也是如此-
诱导的神经保护作用耗尽(时间由经验确定)。这些悬而未决的问题
将在两个目标中进行审查。在SA 1中,我们将使用激光捕获显微切割(LCM)和
酶促甲基测序,以绘制C57 BL/6 J小鼠的全基因组DNA修饰,
数月的有氧运动,这是诱导神经保护所必需的时间。使用所提出的
方法,我们将确定运动相关的变化,在DNA修饰在两个单碱基对,
富集的黑质多巴胺能神经元群体中的基因组区域。在SA 2中,我们将1)
确定自愿运动的神经保护作用是否和/或何时消失,并使用此
信息,2)确定哪些与运动相关的DNA修饰变化在运动后持续存在
停止运动。我们将使用靶向捕获杂交测序来确定运动-
通过LCM分离的SNpc DA神经元的DNA甲基化的相关变化得以维持或逆转
锻炼结束后。这些目标的完成将提供一个候选基因的列表,
对于维持运动诱导的SNpc神经保护至关重要,从而为运动诱导的SNpc神经保护提供了新的靶点。
疾病修饰疗法。
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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Alison Bernstein其他文献
Alison Bernstein的其他文献
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{{ truncateString('Alison Bernstein', 18)}}的其他基金
Diversity Supplement to Dieldrin-induced differential gene methylation and parkinsonian toxicity (R01ES031237)
狄氏剂诱导的差异基因甲基化和帕金森毒性的多样性补充 (R01ES031237)
- 批准号:
10847611 - 财政年份:2023
- 资助金额:
$ 44.38万 - 项目类别:
Dieldrin-induced differential gene methylation and parkinsonian toxicity (R01ES031237)
狄氏剂诱导的差异基因甲基化和帕金森毒性 (R01ES031237)
- 批准号:
10709194 - 财政年份:2022
- 资助金额:
$ 44.38万 - 项目类别:
Dieldrin-induced differential gene methylation and parkinsonian toxicity
狄氏剂诱导的差异基因甲基化和帕金森毒性
- 批准号:
10331048 - 财政年份:2021
- 资助金额:
$ 44.38万 - 项目类别:
Dieldrin-induced differential gene methylation and parkinsonian toxicity
狄氏剂诱导的差异基因甲基化和帕金森毒性
- 批准号:
10115257 - 财政年份:2021
- 资助金额:
$ 44.38万 - 项目类别:
Epigenetic effects of adult and developmental exposure to Parkinsonian toxicants
成人和发育期接触帕金森毒物的表观遗传效应
- 批准号:
9391761 - 财政年份:2017
- 资助金额:
$ 44.38万 - 项目类别:
Epigenetic effects of adult and developmental exposure to parkinsonian toxicants
成人和发育期接触帕金森毒物的表观遗传效应
- 批准号:
8767225 - 财政年份:2014
- 资助金额:
$ 44.38万 - 项目类别:
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