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.

阿尔茨海默氏病（AD），与AD相关的痴呆症（ADRD）和其他神经退行性疾病，例如帕金森氏病（PD）展示致病性基因 - 环境相互作用（GXE），并与暴露于环境化学/病原体/病原体和基因型有关的协同作用。下一代测序的最新进展加剧了发现与阿尔茨海默氏病，与广告相关的痴呆症和帕金森氏病有关的遗传危险因素。然而，发现的遗传因素仅占患者的一小部分，而不是所有患有遗传风险疾病的患者。这对AD/ADRD/PD感到生气，因为它在一个人的一生中与许多协变量有关。为了阐明GXE对疾病的贡献，我们提出了一种基于环境神经毒性的潜在作用原理的方法。以及成人疾病假设的发展起源。我们试图检验以下假设：持续性神经毒性是由于改变了自我持久稳态过程的暴露，从而通过遗传和/或表观遗传手段使对不良毒理学过程的韧性和永久性。具体而言，我们将从印第安纳州北部的同性兄弟姐妹那里收集样本，这些样本在AD/ADRD/PD相关的认知和运动功能障碍表型中表现上有所不同。将血细胞重新编程为人类诱导的多能干细胞（HIPSC）；将它们区分为皮质和中脑谱系；并描述了他们易于诱导与该地区和历史相关的环境危害/有毒物质的神经发育暴露引起的持续神经毒性状态的脆弱性。我们期望在引起的遗传/表观遗传途径水平上识别出一种持续的神经毒性状态，并具有保守的反应。与年龄相关的信号传导网络已被定义为调节健康寿命和衰老的中心途径，因此被预期为GXE风险赋予的共享网络特征。我们的创新方法将利用单细胞基因组学方法和途径分析来识别受试者特异性GXE激活的机制，从而导致持续的神经毒性状态，而受试者大小且FDR较小。以下目的将检验我们的假设并验证共享信号网络：目标1：通过使用成对的阿尔茨海默氏病，与AD相关的痴呆症和帕金森氏病以及健康的群体具有可比性暴露历史的毒性相互作用来确定有毒的毒物相互作用，从而有助于持续的神经毒性；目标2：通过单细胞基因组学和生物信息学比较人口水平数据，确定与建立持续性神经毒性状态相关的遗传途径；目标3：验证使用体内和体外模型持续神经毒性GXE诱导GXE的遗传途径。这项工作旨在了解过去的环境暴露如何通过利用跨学科的学术社区伙伴关系来研究有AD/ADRD/PD风险的老年受试者，从而影响AD/ADRD/PD疾病风险和事件。这些发现还可以确定GXE相互作用的靶标，这些靶标会导致阿尔茨海默氏病，与广告相关的痴呆症和帕金森氏病在我们一生中的风险增加。