Mechanisms of gene-environment interaction in developmental lead exposure leading to Alzheimer's disease phenotypes

发育期铅暴露导致阿尔茨海默病表型的基因-环境相互作用机制

基本信息

批准号：
10591095
负责人：
Jennifer L Freeman
金额：
$ 72.37万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591095
关键词：
Acceleration Address Adopted Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid Fibrils Amyloid beta-Protein Animal Model Attenuated Automobile Driving Behavioral Biological CRISPR interference Calcium Cells Coupled DNA Methylation Data Data Set Development Disease Progression Dose Early Onset Alzheimer Disease Embryo Endosomes Ensure Environment Environmental Exposure Environmental Risk Factor Epidemiology Epigenetic Process Etiology Event Exhibits Exposure to Gene Expression Regulation Genes Genetic Genetic Transcription Glutamate Receptor Glutamates Goals Heavy Metals Heterogeneity Human Image Imaging Device Impairment Knowledge Late Onset Alzheimer Disease Lead Learning Life Literature Long-Term Potentiation Lysosomes Mediating Memory Mental Depression Methylation Mining Modeling Molecular Morphology Mutation Nerve Degeneration Neuraxis Neurologic Neurons Onset of illness Pathway interactions Phenotype Play Predisposition RNA RNA Interference Receptor Gene Research Resolution Risk Risk Factors Role Route Series Spatial Distribution Structure Study models Symptoms Synapses Synaptic Cleft Synaptic plasticity Testing Time Vertebral column Zebrafish antagonist base behavioral phenotyping bisulfite sequencing design disease phenotype epigenetic regulation epigenome epigenomics experimental group experimental study gene environment interaction genetic risk factor induced pluripotent stem cell lead exposure nerve stem cell neurotoxicity novel protein aggregation receptor recycling stem cells success synaptic function tau Proteins time use tool trafficking transcriptome transcriptome sequencing transcriptomics transmission process

项目摘要

Project Summary Developmental exposure to heavy metals, such as lead (Pb), causes systematic damage to the central nervous system and impairs many neurological targets. Some of these biological perturbations, such as altered synaptic plasticity and endosome trafficking, are shared with Alzheimer's Disease (AD). Epigenetic mechanisms, given potency and latency in gene regulation, offer a plausible route to relay impacts from early-life environmental exposure events to AD. The exact molecular mechanism, however, remains elusive. The goal of this proposal is to define the epigenetic mechanism contributing to altered synaptic plasticity arising from developmental Pb exposure addressing the contributions of gene-by-environment (GxE) interactions in accelerating the progression of AD. Our preliminary studies and prior literature suggest persistent alterations in synaptic plasticity, primarily arising from changes in glutamate receptors, including NMDAR and AMPAR. Alterations in endosomal trafficking are also heavily implied. We formulated our central hypothesis that developmental Pb exposure alters the transcription of glutamate receptors via epigenetic regulation affecting synaptic plasticity with the effects exacerbated when coupled with the AD genetic risk factor, SORL1. This GxE interaction compromises endosomal trafficking and glutamate receptor recycling, which eventually leads to the onset of an AD-like phenotype manifested by protein aggregation markers. We adopted a multiplex model including cortical neurons derived from human induced pluripotent stem cells (hiPSCs) and a zebrafish animal model with and without a known late-onset AD (LOAD) risk factor (SORL1). We designed our experiments to dissect contributions from environmental (E), genetic (G), and GxE driven events in altering synaptic plasticity and the manifestation of AD- like phenotypes. We will test our hypothesis in three aims. Aim 1 will elucidate the impact of developmental Pb exposure and SORL1 effects on neuron susceptibility of protein aggregates. Aim 2 will reveal the molecular origin conferring developmental Pb neurotoxicity to an AD-like phenotype. Aim 3 will define subcellular alterations in the post-synapse associated with an AD-like phenotype. Collectively, we will curate time-dependent information about molecular changes in the transcriptome and epigenome, along with alterations in ultrastructure of post-synaptic spine. We will use the aggregated information to infer causative relations among different events by assuming early events are likely to drive late ones. We expect that GxE interactions arising from developmental Pb exposure and SORL1 mutation to induce a phenotype closely resembling AD, followed by SORL1 mutation only, Pb exposure in wild type, and untreated wild type. Furthermore, we will reveal novel targets mediating the latent effects of developmental Pb exposure on neurodegeneration risks via mining of our dataset and verification of the efficacy of underlying epigenetic profiles of glutamate receptors in accelerating AD onset and progression risks. The knowledge generated will enlighten the molecular mechanism of Pb neurotoxcity and connections of early life Pb exposure to AD progression addressing goals of PAR-22-048.

项目概要发育过程中接触铅 (Pb) 等重金属会对中枢神经系统造成系统性损害神经系统并损害许多神经目标。其中一些生物扰动，例如改变突触可塑性和内体运输与阿尔茨海默病 (AD) 共有。表观遗传机制，考虑到基因调控的效力和潜伏期，提供了一条合理的途径来传递早期生命环境的影响 AD 暴露事件。然而，确切的分子机制仍然难以捉摸。该提案的目标是定义导致发育性铅引起的突触可塑性改变的表观遗传机制暴露解决基因与环境（GxE）相互作用在加速 AD 的进展。我们的初步研究和先前的文献表明突触可塑性持续改变，主要由谷氨酸受体的变化引起，包括 NMDAR 和 AMPAR。内体的改变贩卖也有很大的暗示。我们提出了我们的中心假设：发育过程中的铅暴露会改变谷氨酸受体的转录通过表观遗传调控影响突触可塑性及其影响与 AD 遗传风险因素 SORL1 结合时会加剧。这种 GxE 交互会妥协内体运输和谷氨酸受体再循环，最终导致 AD 样疾病的发生由蛋白质聚集标记表现的表型。我们采用了包括皮质神经元的多重模型源自人类诱导多能干细胞 (hiPSC) 和带或不带干细胞的斑马鱼动物模型已知的迟发性 AD (LOAD) 风险因素 (SORL1)。我们设计实验的目的是剖析来自环境 (E)、遗传 (G) 和 GxE 驱动事件改变突触可塑性和 AD 的表现就像表型一样。我们将在三个目标上检验我们的假设。目标 1 将阐明发育 Pb 的影响暴露和 SORL1 对蛋白质聚集体神经元敏感性的影响。目标 2 将揭示分子起源赋予了 AD 样表型的发育性 Pb 神经毒性。目标 3 将定义亚细胞改变位于与 AD 样表型相关的突触后。我们将共同策划与时间相关的有关转录组和表观基因组分子变化以及超微结构变化的信息突触后棘。我们将使用汇总的信息来推断不同事件之间的因果关系假设早期事件可能会导致晚期事件。我们期望 GxE 交互产生于发育性铅暴露和 SORL1 突变诱导出与 AD 非常相似的表型，然后仅 SORL1 突变、野生型中的 Pb 暴露以及未经处理的野生型。此外，我们还将揭晓新颖的通过挖掘我们的神经退行性风险，调节发育性铅暴露对神经退行性风险的潜在影响谷氨酸受体的潜在表观遗传谱在加速中的功效的数据集和验证 AD 发病和进展风险。产生的知识将启发 Pb 的分子机制神经毒性以及生命早期铅暴露与 AD 进展的联系，解决了 PAR-22-048 的目标。