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 Twety Homolog 1(TTYH1)是一种未被研究的蛋白质，通过照亮可药物基因组来鉴定 (IDG)计划。我们目前对TTYH1的了解仅限于它参与神经干细胞的发育 以及神经胶质瘤的侵袭。鉴于缺乏模型系统和遗传工具，分子功能和生物学 与TTYH1相关的通路仍然没有明确的定义。重要的是，基因表达水平的改变 在阿尔茨海默病和帕金森病患者的大脑样本中发现了TTYH1。 因此，阐明TTYH1在脑细胞中的功能作用将有助于理解疾病 发病机制。我们进行了转录分析，确定TTYH1主要表达 在脑星形胶质细胞中。星形胶质细胞是负责处理脂质和提供新陈代谢支持的胶质细胞。 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 TTYH1同源基因定位于溶酶体，溶酶体是执行自噬所需的细胞器。事实上，我们发现 TTYH1促进神经胶质细胞的自噬流量。描述自噬的机械基础 调控将揭示TTYH1的分子功能和生物学作用。我们的数据显示有缺陷的 内化鞘脂的清除是TTYH1溶酶体功能障碍和自噬减少的基础- 神经胶质细胞缺乏。初步的发现告诉我们的中心假设是TTYH1介导了溶酶体 清除鞘脂以促进自噬。为了测试我们的工作假设，我们将利用Rate 星形胶质细胞模型和果蝇模型与工具和实验范式相结合 这个项目。在这次调查结束后，我们将进一步加深对分子的理解。 TTYH1在胶质细胞脂代谢中的作用这个项目的发现也将为理解 溶酶体储存疾病和神经退行性变。