Neurotoxicity of particulate matter and its interaction with APOE in neurodegeneration

颗粒物的神经毒性及其与 APOE 在神经变性中的相互作用

• 批准号: 10590465
• 负责人: Masashi Kitazawa
• 金额: $ 215.91万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590465
• 关键词: Address; Affect; Age; Air; Air Pollution; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Animals; Atrophic; Blood - brain barrier anatomy; Cell Culture Techniques; Cells; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Country; Data; Dementia; Disease; Elderly; Environment; Environmental Hazards; Environmental Impact; Environmental Risk Factor; Etiology; Exhibits; Exposure to; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genotype; Goals; Health; Hippocampus (Brain); Human; Human Genetics; Impaired cognition; Induced pluripotent stem cell derived neurons; Knock-in Mouse; Knowledge; Late Onset Alzheimer Disease; Link; Metals; Modeling; Mus; Mutation; Nerve Degeneration; Neurons; Outcome; Outcome Study; Oxidative Stress; Particulate Matter; Pathogenesis; Pathology; Pathway interactions; Phenotype; Play; Population; Public Health; Reporting; Research; Risk; Role; Senile Plaques; Toxic effect; Transgenic Mice; Wild Type Mouse; ambient air pollution; base; biological adaptation to stress; brain cell; cerebrovascular; clinically relevant; clinically significant; cognitive function; density; design; disease phenotype; entorhinal cortex; excitatory neuron; exposed human population; familial Alzheimer disease; functional genomics; gene environment interaction; genetic risk factor; gray matter; human model; improved; in vitro Model; in vivo; induced pluripotent stem cell; innovation; insight; mouse model; neuroinflammation; neuron loss; neuropathology; neurotoxic; neurotoxicity; novel; overexpression; oxidative damage; resilience; risk variant; single-cell RNA sequencing; tool; transcriptomics; virtual

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common cause of dementia among elderly and is an apparent public health challenge in the U.S. as well as many other countries. Despite the extensive research effort on all aspects of AD, the exact causes of late-onset, sporadic AD remain elusive. Although genetic predispositions including known risk genes from human genetics studies are playing a prominent role in the pathogenesis and etiology of AD, recent growing bodies of evidence strongly suggest an emerging role of environmental contribution, particularly toxic constituents of air pollution including, but not limited to, particulate matter (PM) and metals, to the progression and onset of AD. Thus, it is critical to investigate how air pollution drives neurodegeneration and whether AD risk genes modulate its neurotoxicity and neuronal death, as an empirical example of the gene x environment (GxE) interactions to support the mechanism-based etiology of AD. As increasing number of studies in humans and animal models have confirmed the pivotal role of currently known risk genes and exposure to air pollution, independently or in combination, in AD neuropathology and neurodegeneration, we stay focuses on determining key neurotoxic mechanisms of ambient PM, the most abundant toxic constituents found in the ambient air, which subsequently leads to accelerated neurodegeneration and the clinical onset of AD. The overarching objectives of this study are 1) to comprehensively evaluate neurotoxicity of ambient PM and its environmental risk in a novel mouse model of late-onset AD, and 2) to identify key genes and mechanisms that determine the sensitivity or resilience to neuronal death triggered by PM. In this application, we include several innovative tools, such as a novel mouse model, human iPSC-derived neurons and the CRISPR-based functional genomics, to carefully assess the neurotoxicity of PM, its risk for developing and exacerbating AD phenotypes, and the GxE interactions, all of which could be more clinically relevant and applied to broader general population compared to existing findings from widely used animal models overexpressing familial AD mutations. In our knowledge, proposed in vivo and in vitro models are the best suited models to simulate and evaluate the environmental contribution to late-onset AD in humans. Thus, outcomes from this study maintain high translational significances to understand neurodegenerative mechanisms and the GxE etiology of late-onset AD. Lastly, this proposal is feasible, highly- significant, and highly-relevant to evaluate the etiology and progression of AD in the context of the GxE interactions. We believe that the outcomes could have large impact to the field, while accelerating progress towards understanding the environmental impact on the pathogenesis of AD.

项目摘要/摘要 阿尔茨海默病(AD)是老年人痴呆的最常见原因，是一种明显的公共疾病 美国和其他许多国家的健康挑战。尽管对所有人都进行了广泛的研究 阿尔茨海默病的各个方面，迟发性、散发性阿尔茨海默病的确切原因仍然难以捉摸。尽管遗传易感性 包括人类遗传学研究中的已知风险基因，在发病机制和 阿尔茨海默病的病因学，最近越来越多的证据强烈表明环境因素的作用正在显现 贡献，特别是空气污染的有毒成分，包括但不限于颗粒物(PM) 和金属，与AD的进展和发病有关。因此，调查空气污染是如何驱动的至关重要。 神经退行性变和AD危险基因是否调节其神经毒性和神经元死亡 基因x环境(GxE)相互作用的例子，以支持基于机制的AD病因学。AS 越来越多的人体和动物模型研究证实了目前已知的 独立或联合暴露于空气污染与AD神经病理学和 神经退行性变，我们专注于确定环境PM的关键神经毒性机制，最 在环境空气中发现了大量的有毒成分，这随后导致加速 神经变性与阿尔茨海默病的临床发病这项研究的主要目标是1)至 综合评价环境颗粒物的神经毒性及其环境风险 迟发性阿尔茨海默病，以及2)确定决定对 PM引发的神经元死亡在这个应用程序中，我们包括了几个创新的工具，例如一个新的鼠标 模型、人IPSC来源的神经元和基于CRISPR的功能基因组学，以仔细评估 PM的神经毒性，其发展和加重AD表型的风险，以及GxE相互作用，所有这些 与现有的发现相比，这可能更具有临床相关性，并适用于更广泛的普通人群 来自广泛使用的过度表达家族性AD突变的动物模型。据我们所知，在体内提出的和 体外模型是模拟和评估环境对迟发性疾病贡献的最合适的模型。 人体内的广告。因此，这项研究的结果对理解具有很高的翻译意义 迟发性阿尔茨海默病的神经退变机制和GxE病因。最后，这项建议是可行的，高度- 在GxE的背景下评估AD的病因和进展具有重要和高度相关的意义 互动。我们认为，这些结果可能会对实地产生重大影响，同时加快进展。 有助于了解环境对阿尔茨海默病发病的影响。