Endosomal Microautophagy in Drosophila

果蝇内体微自噬

• 批准号: 10589132
• 负责人: ANDREAS JENNY
• 金额: $ 46.7万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589132
• 关键词: Actins; Affect; Age; Aging; Animal Model; Autophagocytosis; Autophagosome; Award; Binding; Biochemical; Biological; Biological Process; Cardiovascular Diseases; Caring; Cell physiology; Cells; Cellular Stress; Clinical; Complex; Coupled; Cytoplasm; DNA Damage; Data; Dementia; Development; Disease; Disease model; Drosophila genus; Economic Burden; Electron Microscopy; Endosomes; Ensure; Equilibrium; Excision; Fat Body; Functional disorder; Genes; Genetic; Genetic Screening; Glycogen; Goals; Heart; Huntington Disease; Immune System Diseases; Kidney; Kidney Diseases; Life; Liver; Liver diseases; Lysosomes; Machado-Joseph Disease; Malignant Neoplasms; Mammals; Mass Spectrum Analysis; Mediating; Membrane; Mitochondrial Proteins; Modeling; Molecular Chaperones; Multivesicular Body; Nerve Degeneration; Nervous System; Neurodegenerative Disorders; Nobel Prize; Normal Cell; Nutrient; Organelles; Organism; Oxidative Stress; Oxidative Stress Induction; Pathway interactions; Persons; Phosphotransferases; Physiological; Physiology; Predisposition; Process; Protein Biosynthesis; Proteins; Proteome; Publishing; Reactive Oxygen Species; Regulation; Research; Resistance; Reticulum; Risk Factors; Role; Societies; Sorting; Starvation; Stress; System; Testing; Tissues; Transgenic Organisms; Variant; Vesicle; Wiskott-Aldrich Syndrome; age related; coping; energy balance; fly; healthspan; human model; human old age (65+); improved; in vivo; in vivo Model; knock-down; late endosome; lipid metabolism; model organism; multicatalytic endopeptidase complex; novel; overexpression; premature; prevent; protein aggregation; protein degradation; proteostasis; proteotoxicity; receptor; response; sensor; socioeconomics; treatment strategy

Endosomal Microautophagy in Drosophila Caring for an ever aging society represents an increasing socio-economic burden and continuing efforts are required to improve healthspan. Critically, aging is a major ‘risk factor’ for devastating diseases including cancer, immune and cardiovascular diseases, as well as dementias due to neurodegeneration, all of which are strongly affected by a decline in proteostasis. Damaged or altered cytosolic proteins are cleared by the proteasome and autophagy. Importantly, autophagy has the additional role of providing nutrients to cells under stress conditions such as starvation, and is thus essential for energy balance. The removal of damaged organelles and aggregated proteins is thus essential to protect the nervous system, the liver and kidneys against age related disorders. Macroautophagy (MA), chaperone mediated autophagy (CMA) and endosomal microautophagy (eMI) are the three major forms of autophagy. MA engulfs bulk-regions of cytoplasm including organelles in a double membrane vesicle (autophagosome). Autophagosome fusion with lysosomes leads to the degradation of the engulfed material. CMA and eMI mostly degrade proteins containing a targeting motif (KFERQ related sequences) that is recognized by the cytoplasmic Hsc70. We have established a genetic system to study eMI in Drosophila, overcoming a significant hurdle preventing the characterization of the physiological role of eMI, which previously had only been characterized biochemically and by EM in mammals. Hence, we can exploit the genetic power of Drosophila to assess the role of this most recent variant of autophagy. Using our system, we will determine the physiological function and regulation of eMI. In particular, we will identify biological processes controlled by eMI. Furthermore, we will address how kinases we have identified as candidate regulators alter eMI, with a focus on Drosophila models of human neurodegenerative diseases.

果蝇内体微自噬 照顾一个日益老龄化的社会是一个日益沉重的社会经济负担， 需要继续努力改善健康状况。重要的是，老化是一个主要的风险 包括癌症、免疫和心血管疾病在内的毁灭性疾病的“因素”， 以及由于神经变性引起的痴呆症，所有这些都受到 蛋白质稳态下降。受损或改变的胞质蛋白质被清除， 蛋白酶体和自噬。重要的是，自噬具有提供 在饥饿等应激条件下，营养素对细胞是必不可少的， 能量平衡因此，受损细胞器和聚集蛋白质的去除是 对保护神经系统、肝脏和肾脏免受年龄相关的损害至关重要 紊乱 大自噬（MA）、分子伴侣介导的自噬（CMA）和内体自噬 微自噬（microautophagy，eMI）是自噬的三种主要形式。MA吞没体区域 细胞质包括细胞器在一个双膜囊泡（自噬体）。 自噬体与溶酶体融合导致被吞噬物质的降解。 CMA和eMI主要降解含有靶向基序的蛋白质（KFERQ相关 序列），其由细胞质Hsc70识别。我们已经建立了一个基因 系统研究果蝇的eMI，克服了一个重大障碍， eMI的生理作用的表征，这以前只被 在哺乳动物中以生物化学和EM为特征。因此，我们可以利用基因 果蝇的能力来评估这种最新的自噬变体的作用。 使用我们的系统，我们将确定eMI的生理功能和调节。在 特别是，我们将确定由eMI控制的生物过程。此外，我们将 解决我们已经确定为候选调节因子的激酶如何改变eMI，重点是 人类神经退行性疾病的果蝇模型。