Role of autophagy and retromer genes in GLP-1/Notch signaling

自噬和逆转录酶基因在 GLP-1/Notch 信号传导中的作用

• 批准号: 9171257
• 负责人: Alicia Melendez
• 金额: $ 46.2万
• 依托单位: QUEENS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171257
• 关键词: Address; Affect; Aging; Animals; Antithymoglobulin; Autophagocytosis; Autophagosome; Binding; Biochemical; Biogenesis; Biological Assay; Caenorhabditis elegans; Candidate Disease Gene; Cell Culture Techniques; Cell Proliferation; Cell physiology; Cells; Data; Defect; Degradation Pathway; Development; Developmental Process; Diapause; Drosophila genus; Endosomes; Genes; Genetic; Genetic study; Germ Cells; Growth; Image; Infection; Intestines; Laboratories; Life; Link; Longevity; Lysosomes; Mammalian Cell; Mediating; Metabolism; Modeling; Monomeric GTP-Binding Proteins; Nutrient; Organism; Orthologous Gene; Pathway interactions; Persons; Phenotype; Positioning Attribute; Process; Proteins; Recycling; Regulation; Reporter Genes; Role; Signal Pathway; Signal Transduction; Stem cells; Stress; Testing; Time; Tissues; Work; deprivation; developmental genetics; dietary restriction; extracellular; feeding; genetic analysis; glucagon-like peptide 1; in vivo; insulin signaling; loss of function; mutant; notch protein; pathogen; protein function; research study; response; scaffold

PROJECT SUMMARY Cells require a continuous supply of nutrients and energy for growth, metabolism, and survival, and employ dedicated mechanisms to adjust to changes in nutrient availability. Autophagy is a key evolutionarily conserved degradation pathway, by which cellular components are recycled. Autophagy is induced in response to extracellular or intracellular stress by signals that include limited nutrients, growth factor deprivation, ER stress, and/or pathogen infection. Thus, autophagy has to be regulated by signaling pathways that integrate environmental conditions, with developmental progression. A great deal of progress has been made in identifying essential components of the autophagy pathway such as (ATG genes) and their biochemical functions, whereas the mechanisms that regulate autophagy remain poorly understood. We propose here (1) to capitalize on the powerful features of C. elegans genetics to investigate critical protein functions required for autophagy cellular and developmental processes in vivo and, (2) to extend our analysis to mammalian cells. Our preliminary data, and that of others, indicate that autophagy is inappropriately activated in rab-10 mutants, as would be expected if TOR activity depends on RAB-10. Loss of RAB-10 extends lifespan in C. elegans, and the longevity of rab-10 mutants is autophagy dependent. Yet, a mechanism for how RAB-10 regulates TOR, autophagy, and autophagy dependent processes such as germline proliferation or longevity, is not known. We will (i) define the role of RAB-10 in the regulation of TOR, and autophagy, during nutrient replete conditions, dietary restriction, and reduced insulin signaling and (ii) elucidate the role of RAB-10 in two developmental processes: germline proliferation and aging. The C. elegans germline is a valuable model to study the genetic, developmental, and environmental control of germ cell proliferation. These studies are significant because they will advance our understanding of the mechanisms by which autophagy is regulated during development of a multicellular organism, and for control of cell proliferation. They will be informative in regard to both the tissues that require autophagy in development and the proteins involved in the autophagy pathway. Our laboratory is uniquely positioned to pursue this project with our expertise in C. elegans genetics and the study of autophagy.

项目摘要 细胞需要持续的养分和能量，以实现生长，代谢和 生存，并采用专门的机制来适应养分可用性的变化。 自噬是一种关键进化保守的降解途径，细胞通过 组件被回收。自噬响应于细胞外或 细胞内应力通过包括有限养分，生长因子剥夺的信号，ER 压力和/或病原体感染。因此，必须通过信号来调节自噬 将环境条件与发展进展的途径。一个 在确定的基本要素方面取得了很大进步 自噬途径，例如（ATG基因）及其生化功能，而 调节自噬的机制仍然知之甚少。我们在这里提出（1） 利用秀丽隐杆线虫遗传学的强大特征来研究关键蛋白 体内自噬细胞和发育过程所需的功能以及（2） 将我们的分析扩展到哺乳动物细胞。我们的初步数据以及其他数据 表明自噬在RAB-10突变体中被不适当地激活，就像 如果TOR活性取决于RAB-10，则可以预期。 Rab-10的损失延长了C中的寿命。 秀丽隐杆线和Rab-10突变体的寿命是自噬依赖性的。但是，一种机制 对于RAB-10如何调节TOR，自噬和自噬的过程 由于种系增殖或寿命，尚不清楚。我们将（i）定义RAB-10的作用 在养分充满饮食的情况下，在TOR和自噬的调节中 限制和减少胰岛素信号传导，（ii）阐明了RAB-10在两个中的作用 发展过程：种系增殖和衰老。秀丽隐杆线虫种系是 研究细菌的遗传，发育和环境控制的宝贵模型 细胞增殖。这些研究很重要，因为它们会促进我们的 了解在开发过程中自噬的机制 多细胞生物，用于控制细胞增殖。他们将有益 关于两个需要自噬的组织和蛋白质 参与自噬途径。我们的实验室独特地追求这一点 凭借我们在秀丽隐杆线虫遗传学和自噬研究方面的专业知识的项目。