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）通常检测细胞外信号以控制细胞内信号传导。 应答在许多情况下，GPCR检测导致细胞激活的应激， 这个循环过程叫做自噬。在酵母交配途径中，GPCR用于检测 并向潜在的交配对象生长。交配途径启动自噬，尽管 缺乏外部压力。我们假设GPCR激活自噬代表了一种 新的负反馈环，通过增强降解GPCR信号传导， 受体。在Aim 1中，我们将测试信息素信号驱动选择性的假设， 自噬而不是大量自噬，通过Gα激活PI3激酶和 其他信息素特定信号。在目标2中，我们将测试假设，信息素诱导 自噬作为负反馈回路来增强受体脱敏。这些 这些研究将提供对GPCR信号传导与 自噬，这两个系统在酵母和人类之间非常保守， 长期以来，科学研究为人类对自然的理解提供了有意义的进展。 生物学GPCR和自噬相互作用的理解对于理解 目前大量的GPCR和自噬靶向药物的潜在组合效应 用于治疗人类疾病。