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同源1（TTYH1）是通过照明可毒基因组鉴定出的一种蛋白 （IDG）程序。我们目前对TTYH1的了解仅限于它参与神经干细胞的发展 和神经胶质瘤入侵。鉴于缺乏模型系统和遗传工具，分子功能和生物学 与TTYH1相关的途径的定义较差。重要的是，表达水平改变了 在阿尔茨海默氏病和帕金森氏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。我们进行了转录组分析，并确定TTYH1主要表达 在大脑星形胶质细胞中。星形胶质细胞是负责加工脂质并提供代谢支持的神经胶质细胞 致神经元。在果蝇神经胶质中，永生的大鼠星形胶质细胞和原代人星形胶质细胞，我们发现 TTYH1直系同源物本地化为溶酶体，这是进行自噬所需的细胞器。确实，我们发现 TTYH1促进了神经胶质细胞中的自噬通量。描述自噬的机械基础 调节将发现TTYH1的分子功能和生物学作用。我们的数据表明有缺陷 内部鞘脂的清除是溶酶体功能障碍和TTYH1-自噬降低的基础的。 缺乏神经胶质细胞。初步发现介绍了我们的中心假设，即TTYH1介导溶酶体 清除鞘脂以促进自噬。为了检验我们的工作假设，我们将利用老鼠 星形胶质细胞模型和果蝇模型与工具和实验范例相结合 这个项目。在这项研究的结论中，我们将进一步了解分子 TTYH1在神经胶质脂质代谢中的功能。该项目的发现还将提供理解的见解 溶酶体储存疾病和神经变性。