Investigating the convergence of AD genetics on lipid metabolism and microglia regulation

研究 AD 遗传学对脂质代谢和小胶质细胞调节的趋同性

• 批准号: 10288338
• 负责人: Estela Area Gomez
• 金额: $ 43.12万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288338
• 关键词: Age; Agonist; Agreement; Alzheimer' s Disease; Alzheimer' s disease risk; Amplifiers; Amyloid beta-Protein; Antibodies; Binding Proteins; Biology; Cell Culture Techniques; Cells; Cellular Membrane; Chemicals; Cholesterol; Cholesterol Homeostasis; Complex; Correlation Studies; Disease; Environment; Functional disorder; Genes; Genetic; Genetic Diseases; Genetic Variation; Genetic study; Grant; Homeostasis; Human; Immune; Immune response; Impaired cognition; Individual; Inflammation; Inflammatory; Inflammatory Response; Lead; Link; Lipid Binding; Lipids; Membrane; Membrane Microdomains; Metabolism; Methods; Microglia; Modeling; Mutation; Natural Immunity; Nervous system structure; Neurodegenerative Disorders; Outcome; Pathogenesis; Pathology; Pathway interactions; Phenotype; Play; Predisposition; Production; Proteins; Receptor Activation; Receptor Signaling; Regulation; Role; SPI1 gene; Signal Pathway; Signal Transduction; Sphingolipids; Sphingomyelinase; Sphingomyelins; Susceptibility Gene; Toll-like receptors; Variant; cholesterol trafficking; genetic variant; lipid metabolism; macrophage; monocyte; pathogen; peripheral blood; protein expression; protein protein interaction; receptor; response; risk variant; small hairpin RNA; tau Proteins

PROJECT SUMMARY Genetic studies in Alzheimer’s disease (AD) have clearly indicated a role for microglia, the innate immune cells of the CNS, in susceptibility to disease. Moreover, microglia are also implicated in lipid metabolism as a key component of disease mechanism. Microglia are the resident immune cells of the CNS, and are therefore the primary responders to pathogens. More and more correlation studies implicate pathogens in AD pathogenesis or progression. However, the association between genetic alterations specific to microglia, toll-like receptor (TLR) signaling and lipid homeostasis in AD has not been explored in depth. We hypothesize that there is an interaction between the natural function of the genetically associated microglial proteins, lipids and TLR stimulation, the basic biology of which has not been fully elucidated in microglia, the innate immune cells that exist in a lipid rich environment. Among the many factors involved in the regulation of pathogen response pathways, the lipid composition of microglia has been shown to contribute significantly to the regulation of inflammatory signaling. Specifically, cholesterol and sphingomyelin levels have been observed to modulate the expression and distribution of microglia receptors and their downstream targets. We propose that microglia AD risk variants result in disturbances in the regulation of sphingolipid and cholesterol, that in turn, cause the dysregulation of TLR responses and inflammatory phenotypes. We will investigate this hypothesis by examining the effects of microglia AD susceptibility alleles on sphingolipid regulation and lipid raft turnover in a cell culture microglial model. We will also assess the role of sphingolipids in the regulation of microglial signaling via TLR and genetically associated proteins in our microglia model. Results from this proposal will help understand the crosstalk between genetics, TLR-regulation and sphingolipid metabolism and underlying mechanisms by which a microglia induces inflammation through modulation of its membrane in the context of AD.

项目摘要 阿尔茨海默氏病（AD）的遗传学研究已经清楚地表明了小胶质细胞的作用，先天免疫 中枢神经系统的细胞，对疾病的易感性。此外，小胶质细胞也参与脂质代谢， 疾病机制的关键组成部分。小神经胶质细胞是CNS的常驻免疫细胞，因此， 病原体的主要反应者。越来越多的相关研究表明AD与病原体有关 发病机制或进展。然而，与小胶质细胞、Toll样细胞、 在AD中TLR受体信号传导和脂质稳态的研究尚未深入探讨。我们假设 是遗传相关的小胶质细胞蛋白质、脂质和TLR的天然功能之间的相互作用 刺激，其基本生物学尚未在小胶质细胞中完全阐明，小胶质细胞是先天性免疫细胞， 存在于富含脂质的环境中。 在参与调节病原体反应途径的众多因素中，脂质成分 已经显示小胶质细胞对炎症信号的调节有显著贡献。具体地说， 已经观察到胆固醇和鞘磷脂水平调节 小胶质细胞受体及其下游靶点。我们认为小胶质细胞AD风险变异导致 鞘脂和胆固醇调节的紊乱，这反过来又导致 TLR反应和炎症表型。我们将通过检验 在细胞培养的小胶质细胞中，小胶质细胞AD易感性等位基因对鞘脂调节和脂筏周转的影响 模型我们还将评估鞘脂在通过TLR调节小胶质细胞信号传导中的作用， 我们的小胶质细胞模型中的基因相关蛋白。 这项提议的结果将有助于理解遗传学、TLR调控和 鞘脂代谢和小胶质细胞通过以下途径诱导炎症的潜在机制： 在AD的背景下调节其膜。