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。新一代测序的最新进展加快了与阿尔茨海默病、阿尔茨海默病相关的痴呆症和帕金森病相关遗传风险因素的发现。然而，已确定的遗传因素仅占患者的一小部分，并且并非所有具有已确定的遗传风险的患者都会患病。这对于 AD/ADRD/PD 来说是令人恼火的，因为它与一个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神经毒物潜在持续效应原理的方法；以及成人疾病假说的发育起源。我们试图检验这样的假设，即持续性神经毒性是由于暴露改变了自我延续的稳态过程，从而通过遗传和/或表观遗传手段赋予不良毒理学过程弹性和永久性。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样本，这些样本在 AD/ADRD/PD 相关认知和运动功能障碍表型方面存在差异；将血细胞重新编程为人类诱导多能干细胞 (hiPSC)；将它们分化为皮质和中脑谱系；并描述其对因神经发育暴露于与该地区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。我们期望通过在诱发的遗传/表观遗传途径水平上在个体之间共享的保守反应来识别持续的神经毒性状态。 “与年龄相关的信号”网络被定义为调节健康寿命和衰老的中心途径，因此有望成为 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通路分析来识别由受试者特异性 GxE 激活的机制，从而在受试者规模较小和 FDR 较低的情况下导致持续的神经毒性状态。以下目标将检验我们的假设并验证共享的信号网络： 目标 1：使用源自配对阿尔茨海默病、AD 相关痴呆和帕金森病以及具有可比暴露史的健康队列的人类细胞，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：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，确定与建立持续神经毒性状态相关的遗传途径；目标 3：通过体内和体外模型验证 GxE 诱导持续神经毒性的遗传途径。这项工作旨在通过利用跨学科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。这些发现还可能确定 GxE 相互作用的目标，这些目标会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。

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.