Transporters, nutrient sensing and autophagy

转运蛋白、营养传感和自噬

• 批准号: 9980758
• 负责人: Eric H Baehrecke
• 金额: $ 34.34万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980758
• 关键词: Adult; Age; Amino Acid Transporter; Amino Acids; Animals; Apoptosis; Autoimmunity; Autophagocytosis; Biochemical Pathway; Caspase; Catabolic Process; Cell Death; Cell Differentiation process; Cell Survival; Cells; Cellular Morphology; Cessation of life; Data; Defect; Development; Diabetes Mellitus; Disease; Drosophila genus; Equilibrium; FRAP1 gene; Family; Genes; Genetic; Goals; Health; Human; Impairment; Inflammatory; Intestines; Lactate Dehydrogenase; Lysosomes; Malignant Neoplasms; Metabolic; Metabolism; Mitochondria; Modeling; Mutation; Natural regeneration; Nerve Degeneration; Neurodegenerative Disorders; Nutrient; Organism; Pathway interactions; Peptide Hydrolases; Phenotype; Play; Process; Pyruvate; Reactive Oxygen Species; Regulation; Role; Salivary Glands; Signal Transduction; Steroids; Stress; Testing; Tissues; Work; Yeasts; adult stem cell; base; detection of nutrient; human disease; inhibition of autophagy; intestinal homeostasis; knock-down; member; mutant; novel; nutrient deprivation; pyruvate carrier; sensor; solute; stem cell proliferation; stem cells; therapeutic target

ABSTRACT Autophagy is used by all cells to deliver cytoplasmic material to the lysosome for degradation. Significantly, autophagy has been implicated in several human diseases, including inflammatory disorders, cancer and neurodegeneration. Most of what we know about the regulation of autophagy is based on pioneering studies in yeast that defined the core autophagy machinery, but recent studies have revealed that autophagy has unique regulatory mechanisms in higher animals. Our hypothesis is that the regulation of autophagy in multicellular animals involves unknown mechanisms that integrate with known autophagy pathways. In support of our hypothesis, we recently identified previously uncharacterized genes encoding members of the solute transporter (SLC) family that are required for autophagy during salivary gland developmentally programmed cell death, including CG11665/hermes and CG5805. Significantly, hermes encodes a pyruvate transporter that is required for autophagy during salivary gland degradation. hermes mutant salivary glands have elevated mTOR signaling, and decreased mTOR function suppresses the hermes salivary gland phenotype. CG5805 encodes a putative mitochondrial amino acid transporter that is also required for autophagy in salivary glands. Our data suggests that the CG5805 and hermes salivary gland phenotypes are related, possibly through nutrient sensing mechanisms. In addition, hermes mutants have phenotypes suggesting the that these transporters may function in the regulation of autophagy in adult intestine stem cells. Our goal is to characterize the role of these SLCs in autophagy, cell health and death during development and adulthood. Here we propose to: (1) determine how Hermes regulates autophagy during development, (2) investigate CG5805 and its relationship to hermes and autophagy, and (3) characterize the role of transporters and autophagy in adult stem cell and intestine health. The association of autophagy with age-associated disorders illustrates the importance of investigating the relationship between autophagy, cell and animal health.

摘要 自噬被所有细胞用来将细胞质物质运送到溶酶体进行降解。 值得注意的是，自噬与几种人类疾病有关，包括炎症 疾病、癌症和神经退行性变。我们所知道的关于监管的大部分 自噬是基于对酵母的开创性研究，这些研究定义了核心的自噬机制， 但最近的研究表明，自噬在高等生物中具有独特的调控机制。 动物。我们的假设是，多细胞动物中自噬的调节包括 与已知的自噬途径整合的未知机制。为了支持我们的 假说，我们最近发现了以前未描述的基因，编码的成员 唾液腺自噬所需的溶质转运体(SLC)家族 发育程序性细胞死亡，包括CG11665/Hermes和CG5805。值得注意的是， Hermes编码一种丙酮酸转运蛋白，这是唾液腺自噬所必需的 退化。Hermes突变的唾液腺mTOR信号增强，而mTOR信号降低 MTOR功能抑制Hermes唾液腺表型。CG5805编码一个假定的 线粒体氨基酸转运体，也是唾液腺自噬所必需的。我们的 数据表明CG5805和Hermes唾液腺表型可能是相关的 通过营养感应机制。此外，Hermes突变体的表型表明 这些转运蛋白可能在成人肠干自噬的调节中发挥作用 细胞。我们的目标是确定这些SLCs在自噬、细胞健康和死亡中的作用。 在发育和成年期。在这里，我们建议：(1)确定爱马仕如何监管 发育过程中的自噬，(2)调查CG5805及其与Hermes和 自噬，以及(3)表征转运体和自噬在成体干细胞和 肠道健康。自噬与年龄相关疾病的关联说明了 研究自噬、细胞和动物健康之间关系的重要性。