Modeling functional genomics of susceptibility to the persistent effects of environmental toxins in an elderly rural Indiana neurodegenerative cohort

印第安纳州农村老年人神经退行性队列对环境毒素持续影响易感性的功能基因组学建模

• 批准号: 10337727
• 负责人: Aaron B Bowman
• 金额: $ 78.24万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337727
• 关键词: Acute; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Animal Model; Barker Hypothesis; Bioinformatics; Birth; Blood Cells; Caenorhabditis elegans; Cells; Chromatin; Data; Development; Disease; Elderly; Environment; Environmental Exposure; Environmental Hazards; Environmental Risk Factor; Epigenetic Process; Exhibits; Exposure to; Fibrinogen; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic Models; Genetic Risk; Genomic approach; Genomics; Genotype; Geographic Locations; Human; Impaired cognition; Impairment; In Vitro; Incidence; Indiana; Individual; Lead; Life; Link; Longevity; Metals; Midbrain structure; Modeling; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotoxins; Outcome Measure; Paraquat; Parkinson Disease; Pathogenicity; Pathologic; Pathway Analysis; Pathway interactions; Patients; Persons; Pesticides; Phenotype; Population; Population Database; Predisposition; Probability; Process; Property; Rapid screening; Recording of previous events; Research Design; Risk; Role; Rural; Rural Population; Same-sex; Sampling; Siblings; Signal Pathway; Signal Transduction; Statistical Methods; Testing; Time; Toxic Environmental Substances; Toxicology; Toxin; Work; Zebrafish; age related; base; cellular imaging; cohort; community partnership; data mining; disorder risk; early life exposure; environmental chemical; epigenetic profiling; exposed human population; functional genomics; gene environment interaction; genetic risk factor; genome-wide; healthy aging; human disease; in vitro Model; in vivo; induced pluripotent stem cell; innovation; motor disorder; motor impairment; multidimensional data; nerve stem cell; neurotoxic; neurotoxicity; next generation sequencing; novel; pathogen; pollutant; public database; recruit; resilience; response; sex; single-cell RNA sequencing; stem; stem cell differentiation; stem cell model; toxicant; toxicant interaction; transcription factor; transcriptomics

Alzheimer's Disease (AD), AD-related dementias (ADRD) and other neurodegenerative diseases such as Parkinson’s disease (PD) exhibit pathogenic gene-environment interactions (GxE) with synergistic effects of exposure to an environmental chemical/pathogen and genotype. Recent progress in next- generation sequencing has expedited the discovery of genetic risk factors associated with Alzheimer's disease, AD-related dementias and Parkinson’s disease. Yet, identified genetic factors only account for a fraction of patients, and not all patients with the identified genetic risks develop disease. This is exasperated for AD/ADRD/PD as it is convoluted with many covariates over a person’s lifetime. To elucidate the contribution of GxE to disease we propose an approach based on the principles of latent-persistent effects of environmental neurotoxicants; and the developmental origins of adult disease hypothesis. We seek to test the hypothesis that persistent neurotoxicity is due to exposures altering self-perpetuating homeostatic processes that give the resiliency and perpetuity to the adverse toxicological processes by either genetic and/or epigenetic means. Specifically, we will collect samples from same-sex siblings in northern Indiana that phenotypically differ in AD/ADRD/PD relevant cognitive and motor dysfunction phenotypes; reprogram blood cells into human induced pluripotent stem cells (hiPSCs); differentiate them into cortical and midbrain lineages; and characterize their vulnerability to induction of a persistent neurotoxic state caused by neurodevelopmental exposures to environmental hazard/toxicants relevant to this region and history. We expect to identify a persistent neurotoxic state with a conserved response shared across individuals at the level of the genetic/epigenetic pathways evoked. 'Age-related signaling' networks have been defined as central pathways regulating healthy lifespan and aging and are thus expected as a shared network feature conferred by GxE risks. Our innovative approach will leverage single-cell genomics approaches and pathway analysis to identify mechanisms activated by subject-specific GxE to cause a persistent neurotoxic state with only a small subject size and low FDR. The following aims will test our hypothesis and validate the shared signaling networks: Aim 1: Identify subject by toxicant interactions contributing to persistent neurotoxicity using human cells derived from paired Alzheimer's disease, AD-related dementias and Parkinson’s disease and healthy cohort with comparable exposure histories; Aim 2: Identify genetic pathways associated with establishing a persistent neurotoxic state via single-cell genomics and bioinformatic comparisons to population level data; and Aim 3: Validate the genetic pathways of GxE induction of persistent neurotoxicity with in vivo and in vitro models. This work seeks to understand how past environmental exposures influence AD/ADRD/PD disease risk and incidence by utilizing an interdisciplinary academic- community partnership to study elderly subjects at risk for AD/ADRD/PD. The findings may also identify targets of the GxE interactions that contribute to the increased risk of Alzheimer's disease, AD-related dementias and Parkinson’s disease over our lifetime.

阿尔茨海默病 (AD)、AD 相关痴呆 (ADRD) 和其他神经退行性疾病，如帕金森病 (PD)，表现出致病基因-环境相互作用 (GxE)，以及暴露于环境化学物质/病原体和基因型的协同效应。新一代测序加速了与阿尔茨海默病、阿尔茨海默病相关的痴呆症和帕金森病相关的遗传风险因素的发现，然而，已确定的遗传因素仅占一小部分患者，而不是所有患有该病的患者。这对于 AD/ADRD/PD 来说是令人恼火的，因为它与人一生中的许多协变量错综复杂，为了阐明 GxE 对疾病的影响，我们提出了一种基于环境潜在持续影响原理的遗传学方法。我们试图检验以下假设：持续性神经毒性是由于暴露改变了自我维持的稳态过程而导致的。具体来说，我们将从印第安纳州北部的同性兄弟姐妹中收集与 AD/ADRD/PD 相关的认知和运动功能障碍表型不同的样本，将其重新编程为人类血细胞；诱导多能干细胞（hiPSC）；将它们分化为皮质和中脑谱系；并表征它们对因神经发育暴露于与该区域和历史相关的环境危害/毒物而引起的持续神经毒性状态的脆弱性。期望通过在引发的遗传/表观遗传途径水平上个体之间共享的保守反应来识别持续的神经毒性状态，该网络已被定义为调节健康寿命和衰老的中心途径，因此预计是一种共享的。我们的创新方法将利用单细胞基因组学方法和通路分析来识别特定受试者 GxE 激活的机制，从而在受试者规模较小且 FDR 较低的情况下导致持续的神经毒性状态。我们的假设目标 1：使用源自配对阿尔茨海默病、AD 相关痴呆症和帕金森病的人类细胞以及具有可比暴露史的健康队列，通过导致持续神经毒性的毒物相互作用来识别受试者；目标 2：识别相关的遗传途径；通过单细胞基因组学和与群体水平数据的生物信息学比较建立持久的神经毒性状态；目标 3：通过体内和持久的体外模型验证 GxE 诱导神经毒性的遗传途径。这项工作旨在通过利用跨学科的学术界合作伙伴关系来研究面临 AD/ADRD/PD 风险的老年受试者，了解过去的环境暴露如何影响 AD/ADRD/PD 疾病风险和发病率。导致我们一生中患阿尔茨海默病、AD 相关痴呆和帕金森病的风险增加。