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Transporters, nutrient sensing and autophagy

转运蛋白、营养传感和自噬

基本信息

批准号：
10624454
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624454
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 Cytoplasm 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 detection of nutrient gland development 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

项目摘要

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于将细胞质物质递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，包括炎症性疾病，疾病、癌症和神经变性。我们所知道的大多数关于自噬是基于酵母中的开创性研究，其定义了核心自噬机制，但最近的研究表明，自噬在高等动物中具有独特的调节机制，动物我们的假设是，多细胞动物中自噬的调节涉及与已知的自噬途径整合的未知机制。为支持我们的假设，我们最近确定了以前未表征的基因编码的成员，溶质转运蛋白（SLC）家族在唾液腺自噬过程中所需发育性程序性细胞死亡，包括CG 11665/爱马仕和CG 5805。重要的是，爱马仕编码一种丙酮酸转运蛋白，在唾液腺自噬过程中是必需的降解爱马仕突变型唾液腺具有升高的mTOR信号传导，和降低的mTOR信号传导。 mTOR功能抑制爱马仕唾液腺表型。CG 5805编码一个假定的线粒体氨基酸转运蛋白，也是唾液腺中自噬所必需的。我们数据表明，CG 5805和爱马仕唾液腺表型相关，通过营养感应机制。此外，爱马仕突变体的表型表明，这些转运蛋白可能参与了成体肠干细胞自噬的调控细胞我们的目标是描述这些SLC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）确定如何爱马仕调节（2）研究CG 5805与爱马仕的关系，自噬，和（3）表征成体干细胞中转运蛋白和自噬的作用，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的关系的重要性。