Transporters, nutrient sensing and autophagy

转运蛋白、营养传感和自噬

基本信息

批准号：
10417045
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10417045
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

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.

抽象的所有细胞都使用自噬将细胞质材料传递到溶酶体以降解。值得注意的是，自噬已与几种人类疾病有关，包括炎症疾病，癌症和神经退行性。我们对监管的大多数自噬是基于定义核心自噬机械的酵母的开创性研究，但是最近的研究表明，自噬具有较高的独特调节机制动物。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集成的未知机制。支持我们假设，我们最近确定了以前未表征的基因编码的基因唾液腺中自噬所需的溶质转运蛋白（SLC）家族开发编程的细胞死亡，包括CG11665/HERMES和CG5805。显著地，爱马仕（Hermes 降解。爱马仕突变体唾液腺具有升高的MTOR信号传导，并减少 MTOR功能抑制爱马仕唾液腺表型。 CG5805编码推定的线粒体氨基酸转运蛋白也是唾液腺中自噬所必需的。我们的数据表明CG5805和HERMES唾液腺表型是相关的，可能是通过营养感应机制。此外，爱马仕突变体具有表型暗示这些转运蛋白可以在成年肠茎自噬调节中起作用细胞。我们的目标是表征这些SLC在自噬，细胞健康和死亡中的作用在发展和成年期间。在这里我们建议：（1）确定爱马仕如何调节开发过程中的自噬，（2）调查CG5805及其与爱马仕的关系自噬，（3）表征转运蛋白和自噬在成年干细胞中的作用，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关系的重要性。