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.

项目概要 阿尔茨海默氏病 (AD) 的遗传学研究清楚地表明了小胶质细胞（先天免疫）的作用 此外，小胶质细胞还与脂质代谢有关。 小胶质细胞是中枢神经系统的常驻免疫细胞，因此是疾病机制的关键组成部分。 越来越多的相关研究表明 AD 中存在病原体。 然而，小胶质细胞特有的遗传改变之间的关联，类似于Toll。 受体（TLR）信号传导和 AD 中的脂质稳态尚未得到深入研究。 是遗传相关的小胶质细胞蛋白、脂质和 TLR 的自然功能之间的相互作用 刺激，其基本生物学在小胶质细胞中尚未完全阐明，小胶质细胞是先天免疫细胞， 存在于富含脂质的环境中。 在参与病原体反应途径调节的众多因素中，脂质成分 小胶质细胞已被证明对炎症信号的调节有显着贡献。 已观察到胆固醇和鞘磷脂水平可调节 我们认为小胶质细胞受体及其下游靶点会导致 AD 风险变异。 鞘脂和胆固醇的调节紊乱，进而导致 我们将通过检查其影响来研究这一假设。 小胶质细胞 AD 易感性等位基因对细胞培养小胶质细胞中鞘脂调节和筏脂质周转的影响 我们还将评估鞘脂通过 TLR 调节小胶质细胞信号传导的作用。 我们的小胶质细胞模型中的遗传相关蛋白质。 该提案的结果将有助于理解遗传学、TLR 调节和 鞘脂代谢和小胶质细胞通过诱导炎症的潜在机制 AD 背景下对其膜的调节。