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
基本信息
- 批准号:10115257
- 负责人:
- 金额:$ 59.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-21 至 2025-10-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAdultAffectBiologicalBiological AssayBrainCandidate Disease GeneCell Culture TechniquesCorpus striatum structureDNA Modification ProcessDNMT3aDataDevelopmentDieldrinDiseaseDisease susceptibilityDopamineElderlyEnvironmentEnvironmental Risk FactorEpidemiologyEpigenetic ProcessEtiologyExposure toFunctional disorderFundingGene ExpressionGene Expression ProfileGenesGeneticGoalsHDAC9 geneHigh Pressure Liquid ChromatographyImmunohistochemistryIn SituIn VitroIndividualInheritedInjectionsKnowledgeLinkLuciferasesMass Spectrum AnalysisMediatingMediator of activation proteinMethodsMethylationMissionModelingModificationMusMutationNR4A2 geneNational Institute of Environmental Health SciencesNeuritesNeuronsParkinson DiseaseParkinsonian DisordersPathogenesisPathologicPathway AnalysisPathway interactionsPeriodicityPhenotypePlayPredispositionPresynaptic TerminalsRadioactiveRiskRisk FactorsRoleScanningSequencing By HybridizationsSite-Directed MutagenesisSpecificitySystemTestingToxic Environmental SubstancesToxic effectWestern Blottingalpha synucleinbasecell typecytotoxicitydopaminergic neuronepidemiology studyepigenomeexperimental studygenome-widegenomic locusin vivoin vivo Modellaser capture microdissectionmalemethylation patternmotor behaviormouse modelneurotransmissionnigrostriatal pathwaynoveloffspringorganochlorine pesticidepesticide exposureresponsesexsynaptic functionsynucleinopathytooltoxicanttranscriptome sequencinguptake
项目摘要
Project Summary
The majority of Parkinson’s disease (PD) cases are not caused by an inherited monogenic mutation and
disease etiology involves a combination of genetic and environmental factors. Epidemiological studies show
that pesticide exposure, particularly to organochlorine pesticides such as dieldrin, increases risk of sporadic
PD. In a model of increased PD susceptibility, mice exposed to dieldrin during development show male-specific
increased susceptibility to adult exposure to the dopaminergic toxicant MPTP and, in new data from our
NIEHS-funded R21, α-synuclein (α-syn) preformed fibrils (PFFs). The epigenome is a potential mediator of this
relationship between developmental exposures, increased neuronal vulnerability, and adult disease. In line
with this idea, we recently identified sex-specific differential methylation patterns in response to developmental
dieldrin exposure. We hypothesize that dieldrin-induced epigenetic modifications during development
cause changes in gene expression and phenotype that persist into adulthood, altering the sensitivity
to parkinsonian insults and contributing to the development of PD.
To test this hypothesis, we will determine cell-type specific DNA modifications and expression profiles of
previously identified candidate genes in the dieldrin model (Aim 1); analyze the function of synaptic terminals in
our novel dieldrin/PFF two-hit model (Aim 2); and determine if dieldrin or altered expression of candidate genes
affects susceptibility to α-syn PFFs in a dopaminergic neuron cell culture model (Aim 3). The long-term goal
of these experiments is to determine whether dieldrin-associated differentially methylated genes play a
functional role in the biological response to parkinsonian toxicity.
Completion of these aims will further the mission of NIEHS to increase our understanding of how the environment
affects people in order to promote healthier lives, with a specific project goal of connecting exposures with
functional changes in gene expression, neuronal phenotype, and PD susceptibility. The experiments proposed
here will help to establish a biological mechanism linking developmental exposure to late life disease. This project
will also expand our repertoire of tools for interrogating the function of epigenetic changes by establishing an in
vitro experimental paradigm to connect specific epigenetic mechanisms with parkinsonian toxicity. With our in
vivo model that combines developmental exposure with adult PFF injections, we will have a set of experimental
systems in place that will allow us to test a wide variety of exposures, as well as combinations of exposures,
both in vivo and in vitro. Together, this suite of tools will enable us to explore the mechanisms by which PD-
related exposures alter neuronal vulnerability in PD, furthering the goal of NIEHS to understand how combined
exposures affect disease pathogenesis and individual susceptibility.
项目总结
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:
$ 59.23万 - 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:
$ 59.23万 - 项目类别:
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 - 财政年份:2022
- 资助金额:
$ 59.23万 - 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:
$ 59.23万 - 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:
$ 59.23万 - 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:
$ 59.23万 - 项目类别:
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