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

项目摘要 发育期暴露于重金属，如铅（Pb），会导致中枢神经系统的系统性损害。 神经系统和损害许多神经系统的目标。其中一些生物扰动，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， 考虑到基因调控的潜力和潜伏期，提供了一个合理的途径来传递早期生命环境的影响， 暴露于AD。然而，确切的分子机制仍然难以捉摸。这项提案的目的是 明确发育铅引起突触可塑性改变的表观遗传机制， 暴露解决的贡献，基因与环境（GxE）的相互作用，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的持续改变， 主要由谷氨酸受体的变化引起，包括NMDAR和AMPAR。核内体改变 贩卖人口也很严重。我们提出了我们的中心假设，即发育期铅暴露会改变 谷氨酸受体的转录通过表观遗传调控影响突触可塑性的作用 当与AD遗传风险因子SORL 1结合时会加剧。这种GxE相互作用 内体运输和谷氨酸受体再循环，最终导致AD样疾病的发生。 表型表现为蛋白质聚集标志物。我们采用了一个包括皮层神经元的复合模型 来源于人诱导多能干细胞（hiPSC）和具有和不具有 已知的迟发性AD（LOAD）风险因素（SORL 1）。我们设计了实验， 环境（E）、遗传（G）和GxE驱动的事件在改变突触可塑性和AD表现中的作用。 就像表型一样我们将从三个方面来检验我们的假设。目标1将阐明发育铅的影响 暴露和SORL 1对蛋白质聚集体的神经元易感性的影响。目标2将揭示分子 起源赋予发育铅神经毒性的AD样表型。目标3将定义亚细胞改变 与AD样表型相关的突触后。总的来说，我们将策划时间依赖的 关于转录组和表观基因组中分子变化的信息，沿着超微结构的改变 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 通过假设早期事件可能会驱动晚期事件。我们预计，GxE相互作用产生于 发育期铅暴露和SORL 1突变，诱导与AD非常相似的表型， 仅SORL 1突变，野生型和未处理野生型中的铅暴露。此外，我们将揭示小说 目标介导的潜在影响，发展铅暴露对神经变性的风险，通过挖掘我们的 数据集和验证谷氨酸受体的基础表观遗传概况在加速 AD发作和进展风险。产生的知识将启发铅的分子机制 神经毒性和生命早期铅暴露与AD进展的联系，解决PAR-22-048的目标。

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.