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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：
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
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/10707380
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 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

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.

项目总结