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），其具有暴露于环境化学品/病原体和基因型的协同效应。下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风险因素的发现。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发病。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对疾病的贡献，我们提出了一种基于环境神经毒物的潜在持续影响的原则的方法;和成人疾病假说的发展起源。我们试图检验这一假设，即持续的神经毒性是由于暴露改变自我维持的稳态过程，通过遗传和/或表观遗传手段使不利的毒理学过程具有弹性和永久性。具体而言，我们将从北方印第安纳州的同性兄弟姐妹中收集样本，这些兄弟姐妹在AD/ADRD/PD相关认知和运动功能障碍表型方面存在表型差异;将血细胞重编程为人类诱导多能干细胞（hiPSC）;将其分化为皮质和中脑谱系;并描述其易受诱导的持久性神经毒性状态的特点，这种神经毒性状态是由神经发育暴露于环境危害引起的，与该地区和历史有关的有毒物质。我们希望确定一个持久的神经毒性状态与保守的反应，在遗传/表观遗传途径诱发的水平上，在个人之间共享。“与GxE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，因此预计是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确定由受试者特异性GxE激活的机制，从而导致持续的神经毒性状态，并且只有小的受试者规模和低FDR。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：使用源自成对阿尔茨海默病、AD相关痴呆和帕金森病的人细胞和具有可比暴露史的健康队列，通过有助于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;以及目标3：用体内和体外模型探讨GxE诱导持续性神经毒性的遗传途径。这项工作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，研究老年受试者在AD/ADRD/PD的风险。这些发现还可以确定GxE相互作用的靶点，这些靶点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.