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: 10391472
• 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/10391472
• 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）介导了多种激素和神经递质的作用 控制所有哺乳动物细胞中的功能。因此，GPCR是治疗剂的主要靶标。个人 GPCR直接将异源三聚体G蛋白和驱动的亚基的独特完成 下游信号通路以塑造决定GPCR效率的细胞反应。 g和 G亚基与产生细胞反应的作用直接相互作用。我们的实验室主要集中 关于G亚基信号传导和磷脂酶C（PLC）信号的项目，范围从基本分析 生化反应机制，以识别疾病中的作用。在这个建议中，我们试图将所有人结合起来 资助的实验室指示为一个建议。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。这项最初的研究是在 心脏细胞。该项目涉及将这种反应推广到多种细胞类型的证据 表明PI4P是接收器刺激PLC信号传导的主要基材。这有可能改变 接收器依赖性调节磷酸肌醇水解的范例。项目2。这个项目是 定义PLC信号在心力衰竭发展中的作用。我们已经显示了PLC缺失可防止 体外和小鼠肥大的发展。在这里，我们专注于确定机械角色 PLC在调节心脏衰竭的心脏细胞中信号传导。项目3。我们率先确定 调节G蛋白亚基信号的小分子在GPCR的下游，并表明 这些分子具有潜在的治疗效用。在这里，我们将进一步探讨 这些化合物，从使用这些化合物鉴定细胞中新的G蛋白途径的结果后跟进 迁移并确定新型的化学支架以进行治疗发育。