The role of TTYH1 in glial cell autophagy

TTYH1在胶质细胞自噬中的作用

• 批准号: 10666127
• 负责人: Ching-On Wong
• 金额: $ 15.7万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666127
• 关键词: Adult; Alzheimer' s Disease; Amino Acids; Animal Model; Anions; Astrocytes; Autophagocytosis; Autophagosome; Biological; Biological Models; Biological Process; Brain; Cell model; Cells; Cellular Metabolic Process; Critical Pathways; Cryoelectron Microscopy; Cytosolic Phospholipase A2; Data; Disease; Drosophila genus; Functional disorder; Future; Genetic; Genome; Glioma; Glucosylceramides; Goals; Health; Homeostasis; Homologous Gene; Homologous Protein; Human; Hydrophobicity; Hyperactivity; Impairment; Invaded; Investigation; Ion Channel; Knowledge; Lactosylceramides; Lipid Binding; Lipids; Lysosomal Storage Diseases; Lysosomes; Measures; Mediating; Membrane; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Molecular Probes; Nerve Degeneration; Neuroglia; Neurons; Organelles; Orthologous Gene; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Phenotype; Positioning Attribute; Process; Protein Family; Proteins; Rattus; Regulation; Role; Sampling; Site; Sphingolipids; Stem Cell Development; Testing; Transgenic Organisms; animal data; brain cell; ceramide 1-phosphate; insight; lipid metabolism; lipid transport; lipidomics; member; nerve stem cell; neuroinflammation; overexpression; programs; tool; transcriptomics

Project Summary Tweety Homolog 1 (TTYH1) is an understudied protein identified by the Illuminating the Druggable Genome (IDG) Program. Our current knowledge on TTYH1 is limited to its involvement in neural stem cell development and glioma invasion. Given the lack of model system and genetic tools, molecular function and biological pathways that are associated with TTYH1 remain poorly defined. Importantly, altered expression levels of TTYH1 have been found in brain samples from Alzheimer’s disease and Parkinson’s disease patients. Therefore, elucidating the functional roles of TTYH1 in brain cells will aid in the understanding of disease pathogenesis. We performed transcriptomic analyses and determined that TTYH1 is predominantly expressed in brain astrocytes. Astrocytes are glial cells responsible for processing lipids and providing metabolic support to neurons. In Drosophila glia, immortalized rat astrocytes, and primary human astrocytes, we found that TTYH1 orthologs are localized to lysosome, the organelle required for performing autophagy. Indeed, we found that TTYH1 facilitates autophagic flux in glial cells. Delineating the mechanistic underpinnings of autophagy regulation will uncover the molecular function and biological role of TTYH1. Our data suggest that defective clearance of internalized sphingolipids underlies lysosomal dysfunction and diminished autophagy in TTYH1- deficient glial cells. The preliminary findings inform our central hypothesis that TTYH1 mediates lysosomal clearance of sphingolipids to facilitate autophagy. To test our working hypothesis, we will leverage rat astrocytic cell model and Drosophila model combined with tools and experimental paradigms developed for this project. At the conclusion of this investigation, we will have furthered our understanding of the molecular function of TTYH1 in glial lipid metabolism. Findings from this project will also offer insights to understanding lysosomal storage diseases and neurodegeneration.

项目摘要 Tweety同系物1（TTYH 1）是一种未充分研究的蛋白质，由照亮可药用基因组鉴定 (IDG)程序.我们目前对TTYH 1的了解仅限于其参与神经干细胞发育 和胶质瘤侵袭。由于缺乏模型系统和遗传工具，分子功能和生物学特性 与TTYH 1相关的通路仍然不清楚。重要的是，改变的表达水平， TTYH 1已经在阿尔茨海默病和帕金森病患者的大脑样本中发现。 因此，阐明TTYH 1在脑细胞中的功能作用将有助于理解疾病 发病机制我们进行了转录组学分析，并确定TTYH 1主要表达于 在大脑星形胶质细胞中。星形胶质细胞是负责处理脂质和提供代谢支持的神经胶质细胞 到神经元在果蝇胶质细胞、永生化大鼠星形胶质细胞和原代人类星形胶质细胞中，我们发现， TTYH 1直系同源物定位于溶酶体，溶酶体是进行自噬所需的细胞器。我们发现， TTYH 1促进神经胶质细胞中的自噬流。描述自噬的机制基础 调控将揭示TTYH 1的分子功能和生物学作用。我们的数据显示， TTYH 1 - 10细胞内内化鞘脂的清除是溶酶体功能障碍和减少自噬的基础。 缺乏神经胶质细胞。初步研究结果告知我们的中心假设，TTYH 1介导溶酶体 清除鞘脂以促进自噬。为了验证我们的假设，我们将利用 星形胶质细胞模型和果蝇模型，结合开发的工具和实验范例， 这个项目在这项调查的结论，我们将进一步了解分子 TTYH 1在胶质细胞脂质代谢中的作用该项目的发现也将为理解 溶酶体贮积病和神经变性。