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

阿尔茨海默病（AD）， AD相关性痴呆（ADRD）和其他神经退行性疾病，如帕金森病（PD）表现出致病性基因-环境相互作用（GxE），暴露于环境化学物质/病原体和基因型具有协同效应。新一代测序的最新进展加速了与阿尔茨海默病、ad相关痴呆和帕金森病相关的遗传危险因素的发现。然而，确定的遗传因素只占一小部分患者，并不是所有具有确定的遗传风险的患者都会患上疾病。对于AD/ADRD/PD来说，这是令人恼火的，因为它涉及到一个人一生中的许多协变量。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物潜在持续效应原理的方法；以及成人疾病的发展起源假说。我们试图验证持续性神经毒性是由于暴露改变了自我延续的内稳态过程，通过遗传和/或表观遗传手段使不良毒理学过程具有弹性和持久性。具体来说，我们将收集来自印第安纳州北部的同性兄弟姐妹的样本，这些兄弟姐妹在AD/ADRD/PD相关的认知和运动功能障碍表型上存在显着差异；将血细胞重编程为人类诱导多能干细胞（hiPSCs）；将它们区分为皮层和中脑谱系；并描述其易受持续性神经毒性状态诱导的脆弱性，这种状态是由神经发育暴露于与该地区和历史相关的环境危害/毒物引起的。我们期望在遗传/表观遗传通路的水平上确定持久的神经毒性状态，并在个体之间共享保守反应。“年龄相关信号”网络被定义为调节健康寿命和衰老的中心通路，因此被认为是GxE风险所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确定由受试者特异性GxE激活的机制，从而在受试者规模小、FDR低的情况下导致持续的神经毒性状态。以下目标将验证我们的假设并验证共享的信号网络：目标1：使用来自配对阿尔茨海默病，ad相关痴呆和帕金森病的人类细胞和具有可比暴露史的健康队列，通过毒物相互作用确定导致持续神经毒性的受试者；目标2：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，确定与建立持续性神经毒性状态相关的遗传途径；目的3：通过体内和体外模型验证GxE诱导持续性神经毒性的遗传途径。本研究旨在了解过去的环境暴露如何影响AD/ADRD/PD疾病的风险和发病率，利用跨学科的学术-社区合作伙伴关系研究AD/ADRD/PD风险的老年受试者。研究结果还可能确定GxE相互作用的目标，这些相互作用会增加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。

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.