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(GPCRs)通常通过检测细胞外信号来控制细胞 回应。在许多情况下，GPCRs检测导致细胞激活的压力 回收过程被称为自噬。在酵母交配途径中，GPCRs被用来检测 并成长为潜在的交配伙伴。交配途径启动自噬，尽管 缺乏外部压力。我们假设自噬的gpr激活代表一种 一种新的负反馈环路，它通过增强降解率来减少GPCR信号 感受器。在Aim1中，我们将测试信息素信号驱动选择性 自噬而不是大量自噬通过结合Gα激活PI3Kinase和 其他信息素特定的信号。在目标2中，我们将检验信息素诱导 自噬作为一个负反馈环来增强受体的脱敏作用。这些 研究将提供一个分子上的了解之间的相互作用的gpr信号和 自噬，酵母和人类之间非常保守的两个系统，其中酵母 研究为人类的理解提供了有意义的进步已经有很长的历史了 生物学。理解gpr和自噬的相互作用对于理解 目前靶向药物的多种gpr和自噬的潜在联合作用 用来治疗人类疾病。