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

• 批准号: 10707380
• 负责人: Jennifer L Freeman
• 金额: $ 75.05万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 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/10707380
• 关键词: Acceleration; Address; Adopted; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid Fibrils; Amyloid beta-Protein; Animal Model; Attenuated; Automobile Driving; Behavioral; Biological; CRISPR interference; Calcium; Cells; Central Nervous System; 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; Heritability; Heterogeneity; Human; 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; 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; abeta accumulation; antagonist; 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; postsynaptic; progression risk; protein aggregation; receptor recycling; success; superresolution imaging; synaptic function; tau aggregation; time use; tool; trafficking; transcriptome; transcriptome sequencing; transcriptomics; transmission process

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.

项目摘要 发育性暴露于重金属（例如铅（PB）），会对中央造成系统损害 神经系统并损害许多神经系统靶标。这些生物扰动中的一些，例如改变 突触可塑性和内体贩运与阿尔茨海默氏病（AD）共享。表观遗传机制， 鉴于基因调节的效力和延迟，提供了一条合理的途径，以影响早期生活的影响 暴露于广告。但是，确切的分子机制仍然难以捉摸。该提议的目的是 定义促进发育性PB产生的突触可塑性改变的表观遗传机制 解决基因环境（GXE）相互作用的贡献的暴露在加速 AD的进展。我们的初步研究和先前的文献表明突触可塑性的持续改变， 主要是由包括NMDAR和AMPAR在内的谷氨酸受体的变化引起的。内体的改变 贩运也被严重暗示。我们提出了中心假设，即发育PB暴露会改变 通过表观遗传调节对谷氨酸受体的转录，影响突触可塑性与影响 与AD遗传危险因子SORL1结合时会加重。这种GXE相互作用妥协 内体贩运和谷氨酸受体回收，最终导致广告样的发作 表型由蛋白质聚集标记表现出来。我们采用了包括皮质神经元在内的多重模型 源自人类诱导的多能干细胞（HIPSC）和有和没有斑马鱼模型 已知的晚期AD（负载）风险因素（SORL1）。我们设计了我们的实验，以剖析 环境（E），遗传（G）和GXE驱动的事件改变了突触可塑性以及AD-的表现 像表型。我们将以三个目标来检验我们的假设。 AIM 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。 AIM 2将揭示分子 起源将发育性PB神经毒性赋予类似AD的表型。 AIM 3将定义亚细胞的变化 在与广告样表型相关的后肿块中。总的来说，我们将策划时间依赖于时间 有关转录组和表观基因组分子变化的信息，以及超微结构的改变 突触后脊柱。我们将使用汇总信息来推断不同事件之间的病因关系 通过假设早期事件可能会驱动晚期。我们期望GXE互动来自 发育性PB暴露和SORL1突变以诱导与AD相似的表型，其次是 仅SORL1突变，野生型的PB暴露和未处理的野生型。此外，我们将揭示小说 针对介导发育性PB暴露对神经变性风险的潜在影响，通过我们的挖掘 数据集和谷氨酸受体基础表观遗传概况在加速中的疗效的验证 广告发作和进展风险。产生的知识将启发PB的分子机制 PB 22-048目标的神经毒性和早期生命早期PB暴露于AD进展的联系。