Regulation of Apolipoprotein Secretion by TTYH1 and tweety in Glial Cells

胶质细胞中 TTYH1 和 tweety 对载脂蛋白分泌的调节

• 批准号: 10085308
• 负责人: Ching-On Wong
• 金额: $ 15.6万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10085308
• 关键词: Address; Alleles; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Animal Model; Apolipoprotein E; Apolipoproteins; Astrocytes; Blood Circulation; Brain; Data; Drosophila genus; Exhibits; Expression Profiling; Genes; Genotype; Goals; Homologous Gene; Human; Lipids; Lipoproteins; Longevity; Mammalian Cell; Mammals; Metabolic; Microglia; Modeling; Mus; Nerve Degeneration; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurologic Dysfunctions; Neurons; Oxidative Stress; Pathway interactions; Phenotype; Play; Process; Protein Isoforms; Proteins; Regulation; Resistance; Role; Testing; Variant; Vesicle; apolipoprotein D; apolipoprotein E-3; biological adaptation to stress; cell type; design; experimental study; fly; genetic risk factor; insight; interest; lipid metabolism; lipid transport; locomotor deficit; mutant; neurodegenerative phenotype; new therapeutic target; trafficking; transcriptomics; Address; Alleles; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Animal Model; Apolipoprotein E; Apolipoproteins; Astrocytes; Blood Circulation; Brain; Data; Drosophila genus; Exhibits; Expression Profiling; Genes; Genotype; Goals; Homologous Gene; Human; Lipids; Lipoproteins; Longevity; Mammalian Cell; Mammals; Metabolic; Microglia; Modeling; Mus; Nerve Degeneration; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurologic Dysfunctions; Neurons; Oxidative Stress; Pathway interactions; Phenotype; Play; Process; Protein Isoforms; Proteins; Regulation; Resistance; Role; Testing; Variant; Vesicle; apolipoprotein D; apolipoprotein E-3; biological adaptation to stress; cell type; design; experimental study; fly; genetic risk factor; insight; interest; lipid metabolism; lipid transport; locomotor deficit; mutant; neurodegenerative phenotype; new therapeutic target; trafficking; transcriptomics

Project Summary Lipid transport is integral to lipid metabolism and stress response in the central nervous system. Lipoproteins are the major intercellular lipid carrier between neurons and glia. The lipid composition, trafficking, and metabolic fate of lipoproteins are largely dependent on the associated apolipoproteins. Disrupted function of apolipoproteins result in neurodegenerative phenotypes in animal models of neurodegeneration. Furthermore, allelic variation of the Apolipoprotein E (APOE) gene is the major risk factor of Alzheimer's Disease (AD). Glial cells such as astrocytes and microglia are the major cell types that process and secret ApoE in the nervous system. Glia also serve a protective role by mitigating neuronal oxidative stress, a common hallmark of AD and other neurodegenerative diseases. While it is well established that apolipoproteins play critical roles in lipid metabolism, our understanding of apolipoprotein transport in the nervous system is still limited. In addition, whether glial cells couple oxidative stress response with apolipoprotein trafficking remains to be tested. Since intracellular vesicular compartments are required for the trafficking of apolipoproteins, we hypothesize that endolysosomal proteins functionally interact with ApoE in brain. By examining the expression profile of putative endolysosomal genes, we identify Tweety Homolog 1 (TTYH1) that co-expresses with APOE in human brain. Preliminary studies performed in mammalian cells and Drosophila mutant of tty, homolog of TTYH1, suggest that tty and TTYH1 are required for the secretion of apolipoproteins, such as ApoD and ApoE, from glia and regulating oxidative stress in the nervous system. tty mutant flies show shortened lifespan and locomotor phenotypes. Our central hypothesis is that tty and TTYH1 regulate apolipoprotein trafficking to mitigate oxidative stress in glial cells. In this proposal, we aim to address the roles of tty and TTYH1 in: 1) the secretion of apolipoprotein from glia to circulation; and 2) mitigating glial oxidative stress via apolipoprotein secretion. Our long-term goal is to delineate specific pathway that regulate ApoE/D processing and secretion in glial cells and reveal new therapeutic targets for AD and related dementias.

项目摘要 脂质转运是中枢神经系统中脂质代谢和应力反应不可或缺的一部分。脂蛋白 是神经元和神经胶质之间的主要细胞间脂质载体。脂质成分，贩运和 脂蛋白的代谢命运在很大程度上取决于相关的载脂蛋白。中断的功能 载脂蛋白导致神经退行性动物模型中的神经退行性表型。此外， 载脂蛋白E（APOE）基因的等位基因变异是阿尔茨海默氏病（AD）的主要危险因素。神经胶质 星形胶质细胞和小胶质细胞等细胞是在神经中处理和秘密apoE的主要细胞类型 系统。 Glia还通过减轻神经氧化应激，AD和 其他神经退行性疾病。虽然众所周知，载脂蛋白在脂质中起关键作用 代谢，我们对神经系统中载脂蛋白转运的理解仍然有限。此外， 神经胶质细胞是否将氧化应激反应与载脂蛋白运输持续尚待测试。自从 载脂蛋白的运输需要细胞内囊泡室，我们假设 内溶性蛋白质在大脑中与APOE的功能相互作用。通过检查推定的表达曲线 内溶性基因，我们识别出与人脑中APOE共表达的Tweety同源1（TTYH1）。 在TTYH1同源物TTY的哺乳动物细胞和果蝇突变体中进行的初步研究表明 TTY和TTYH1是从Glia和 调节神经系统中的氧化应激。 TTY突变蝇显示寿命和运动缩短 表型。我们的中心假设是TTY和TTYH1调节载脂蛋白的运输以减轻 神经胶质细胞中的氧化应激。在此提案中，我们旨在解决TTY和TTYH1的作用：1） 从神经胶质到循环的载脂蛋白； 2）通过载脂蛋白分泌缓解神经胶质氧化应激。 我们的长期目标是描述调节APOE/D处理和分泌胶质细胞的特定途径 并揭示有关AD和相关痴呆症的新治疗靶标。