Mechanisms of GPCR-induced Autophagy

GPCR 诱导自噬的机制

基本信息

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
项目类别：
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

项目摘要

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来控制细胞在许多情况下，GPCR 检测导致细胞激活的压力。在酵母交配途径中，GPCR 用于检测称为自噬的回收过程。尽管交配途径启动了自噬，但仍增加了对交配伙伴的潜力。我们勇敢地认为 GPCR 激活自噬代表了一种新型负反馈环路，通过增强降解来减少 GPCR 信号传导在 Aim1 中，我们将测试信息素信号驱动选择性的假设。通过 Gα 激活 PI3 激酶和在目标 2 中，我们将检验信息素诱导的假设。自噬作为负反馈回路增强受体脱敏。研究将从分子角度理解 GPCR 信号传导与自噬，酵母和人类之间保存完好的两个系统，其中酵母研究在为理解人类提供有意义的进展方面有着悠久的历史了解 GPCR 和自噬相互作用对于理解生物学非常重要。目前无数GPCR和自噬靶向药物的潜在组合效应用于治疗人类疾病。