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，已识别的遗传因素只占患者的一小部分，并不是所有具有已识别的遗传风险的患者都会患上疾病。这对于AD/ADRD/PD来说是令人恼火的，因为它在人的一生中与许多协变量交织在一起。为了阐明GxE在疾病中的作用，我们提出了一种基于环境神经毒物的潜在-持久效应的原理和成人疾病的发育起源假说的方法。我们试图测试这一假说，即持续性神经毒性是由于暴露改变了自我持续的动态平衡过程，从而通过遗传和/或表观遗传手段赋予不利毒理学过程以弹性和永久性。具体地说，我们将收集印第安纳州北部AD/ADRD/PD相关认知和运动功能障碍表型表型不同的同性兄弟姐妹的样本；将血细胞重新编程为人类诱导的多能干细胞(HiPSCs)；将其分化为皮质和中脑谱系；并表征他们对神经发育暴露于与该地区和历史相关的环境危害/毒物引起的持续性神经毒性状态的易感性。我们希望在诱发的遗传/表观遗传途径水平上，确定一种持续的神经毒性状态，并在个体之间共享保守的反应。“年龄相关信号”网络被定义为调节健康寿命和衰老的中央通路，因此被认为是GxE风险赋予的一个共享网络特征。我们的创新方法将利用单细胞基因组学方法和路径分析来确定特定受试者GxE激活的机制，从而在仅有小受试者规模和低FDR的情况下导致持续性神经毒性状态。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：使用来自配对的阿尔茨海默病、AD相关痴呆和帕金森病的人类细胞以及具有可比较的暴露史的健康队列，通过毒物相互作用来确定主题；目标2：通过单细胞基因组学和与人群水平的生物信息学比较来确定与建立持久神经毒性状态相关的遗传路径；以及目标3：用体内和体外模型验证GxE诱导持久神经毒性的遗传途径。这项工作试图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，通过利用跨学科的学术-社区合作伙伴关系来研究AD/ADRD/PD的高危老年人。这些发现还可能确定GxE相互作用的靶点，这些相互作用导致我们一生中患阿尔茨海默病、AD相关痴呆和帕金森氏症的风险增加。

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.