Understanding and Manipulating Phospholipase C and G Protein beta gamma subunit Signaling Networks

了解和操作磷脂酶 C 和 G 蛋白 β γ 亚基信号网络

• 批准号: 9922940
• 负责人: Alan V. Smrcka
• 金额: $ 59.28万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922940
• 关键词: Biochemical Reaction; Cardiac; Cells; Chemicals; Complement; Development; Disease; Funding; G-Protein-Coupled Receptors; G-protein Beta gamma; GTP-Binding Proteins; Heart failure; Heterotrimeric G Protein Subunit; Hormones; Hydrolysis; Hypertrophy; Immunity; In Vitro; Individual; Laboratories; Ligands; Mammalian Cell; Mediating; Modeling; Mus; Neurotransmitters; Pathway interactions; Phosphatidylinositols; Phospholipase C; Process; Protein Subunits; Reaction; Regulation; Role; Shapes; Signal Pathway; Signal Transduction; Signaling Protein; Therapeutic; cardiogenesis; cell motility; cell type; citrate carrier; follow-up; novel; novel therapeutics; phosphatidylinositol 4-phosphate; phospholipase C gamma; prevent; receptor; response; scaffold; small molecule; targeted treatment; therapeutic development

Abstract G protein-coupled receptors (GPCRs) mediate the actions of a wide variety of hormones and neurotransmitters to control functions in all mammalian cells. As such, GPCRs are major targets of therapeutics. Individual GPCRs directly couple to distinct complements of heterotrimeric G protein  and  subunits that drive downstream signaling pathways to shape the cellular responses that determine GPCR efficacy. Both G and G subunits interact directly with effectors to produce cellular responses. Our laboratory has focused largely on G subunit signaling and Phospholipase C (PLC) signaling on projects ranging from analysis of basic biochemical reaction mechanisms to identification of roles in disease. In this proposal we seek to combine all of the funded laboratory directions into one proposal. Project 1. We were recently the first to demonstrate that phosphatidylinositol 4-phosphate is a substrate for PLC activity in cells. This initial study was performed in cardiac cells. This project is concerned with generalizing this reaction to multiple cell types with the evidence suggesting that PI4P is a major substrate for receptor stimulated PLC signaling. This has the potential to alter the paradigm for receptor-dependent regulation of phosphoinositide hydrolysis. Project 2. This project is to define roles for PLC signaling in the development of heart failure. We have shown the PLC deletion prevents development of hypertrophy in vitro and in mice. Here we are focused on identifying the mechanistic roles for PLC signaling in cardiac cells that regulate heart failure. Project 3. We have pioneered the identification of small molecules that modulate G protein  subunit signaling downstream of GPCRs and have shown that these molecules have potential therapeutic utility. Here we will further explore the mechanism of action of these compounds, follow up from results of using these compounds to identify new G protein pathways in cell migration and identify novel chemical scaffolds for therapeutic development.

抽象的 G 蛋白偶联受体 (GPCR) 介导多种激素和神经递质的作用 控制所有哺乳动物细胞的功能因此，GPCR 是个体治疗的主要目标。 GPCR 直接与异源三聚体 G 蛋白 α 和 β 亚基的不同互补体偶联，驱动 下游信号通路塑造决定 GPCR 功效的细胞反应。 G 亚基直接与效应器相互作用以产生细胞反应。 G 亚基信号传导和磷脂酶 C (PLC) 信号传导的项目范围从基本分析到 确定疾病中作用的生化反应机制在本提案中，我们寻求将所有内容结合起来。 将资助的实验室方向纳入一个提案项目 1。我们最近是第一个证明这一点的人。 磷脂酰肌醇 4-磷酸是细胞中 PLC 活性的底物。这项初步研究是在 该项目旨在通过证据将这种反应推广到多种细胞类型。 表明 PI4P 是受体刺激的 PLC 信号传导的主要底物，这有可能改变。 磷酸肌醇水解的受体依赖性调节范例项目 2。该项目旨在 定义 PLC 信号传导在心力衰竭发展中的作用 我们已经证明 PLC 删除可以预防心力衰竭。 体外和小鼠体内肥大的发展在这里，我们重点关注确定其机制作用。 心脏细胞中调节心力衰竭的 PLC 信号传导。项目 3。我们率先鉴定了 调节 GPCR 下游 G 蛋白  亚基信号传导的小分子，并已表明 这些分子具有潜在的治疗效用，在这里我们将进一步探讨其作用机制。 这些化合物，根据使用这些化合物识别细胞中新的 G 蛋白途径的结果进行跟踪 迁移并确定用于治疗开发的新型化学支架。