Mechanisms of GPCR-induced Autophagy

GPCR 诱导自噬的机制

• 批准号: 10557029
• 负责人: Joshua Brian Kelley
• 金额: $ 25.95万
• 依托单位: UNIVERSITY OF MAINE ORONO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-05 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557029
• 关键词: Attenuated; Autophagocytosis; Binding; Cell physiology; Cells; Cellular biology; Cues; Development; Disease; Drug Receptors; Drug Targeting; Endocytosis; Feedback; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein Regulators; GTP-Binding Proteins; Health; Human; Human Biology; Hyperactivity; Mediating; Molecular; Morphogenesis; Mutation; Organelles; Output; PIK3CG gene; Partner in relationship; Pathway interactions; Pharmaceutical Preparations; Pheromone; Phosphorylation; Physiological; Process; Proteins; Receptor Activation; Receptor Signaling; Recording of previous events; Recycling; Regulation; Research; Role; Signal Induction; Signal Pathway; Signal Transduction; Stress; System; Testing; Tissues; Ubiquitin family; Vacuolar Protein Sorting; Vacuole; Visualization; Yeast Model System; Yeasts; cell behavior; cell growth regulation; combat; combinatorial; desensitization; detector; epsin; extracellular; genetic regulatory protein; human disease; immune function; member; mutant; novel; novel strategies; receptor; receptor internalization; response; sorting nexins; spatiotemporal; stressor; tumor progression; yeast genetics

G-protein coupled receptors (GPCRs) commonly detect extracellular signals to control cellular responses. In many cases, GPCRs detect stresses that lead to activation of the cellular recycling process called autophagy. In the yeast mating pathway, GPCRs are used to detect and grow towards potential mating partners. The mating pathway initiates autophagy, despite the lack of an external stress. We hypothesize that GPCR activation of autophagy represents a novel negative feedback loop that reduces GPCR signaling through enhanced degradation of the receptor. In Aim1 we will test the hypothesis that pheromone signaling drives selective autophagy rather than bulk autophagy through a combination of Gα activation of PI3 Kinase and other pheromone specific signals. In Aim 2 we will test the hypothesis that pheromone induced autophagy serves as a negative feedback loop to enhance receptor desensitization. These studies will provide a molecular understanding of the interplay between GPCR signaling and autophagy, two systems that are well conserved between yeast and humans and in which yeast research has a long history of providing meaningful advances in the understanding of human biology. The understanding of GPCR and autophagy interactions is important to understanding the potential combinatorial effects of the myriad GPCR and autophagy targeting drugs currently used to treat human disease.

G蛋白偶联受体（GPCR）通常检测到细胞外信号以控制细胞 回答。在许多情况下，GPCR检测到导致细胞激活的应力 回收过程称为自噬。在酵母交配途径中，GPCR用于检测 并成长为潜在的交配伙伴。交配途径启动自噬，目的地 缺乏外部压力。我们假设自噬的GPCR激活代表 新颖的负反馈循环通过增强的降解来降低GPCR信号传导 接收器。在AIM1中，我们将测试信息素信号传导选择性的假设 通过PI3激酶的Gα激活和 其他信息素特定信号。在AIM 2中，我们将测试信息素诱导的假设 自噬是负反馈循环，以增强接收器脱敏。这些 研究将对GPCR信号和 自噬，两个系统在酵母和人类之间都很好地保存，其中酵母 研究在对人类的理解方面有有意义的进步有悠久的历史 生物学。对GPCR和自噬相互作用的理解对于理解很重要 目前，无数GPCR和自噬靶向药物的潜在组合作用 用于治疗人类疾病。