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.

摘要 G蛋白偶联受体（GPCRs）介导多种激素和神经递质的作用 来控制所有哺乳动物细胞的功能因此，GPCR是治疗剂的主要靶标。个人 GPCR直接偶联到异源三聚体G蛋白A和B亚基的不同互补物， 下游信号传导途径，以形成决定GPCR功效的细胞反应。G和 G蛋白亚基直接与效应子相互作用以产生细胞反应。我们的实验室主要关注 对G蛋白亚基信号传导和磷脂酶C（PLC）信号传导等项目进行了基础分析， 生化反应机制，以确定在疾病中的作用。在本提案中，我们寻求将所有联合收割机 把实验室的资金投入到一个项目中。项目1。我们最近第一个证明， 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 心肌细胞这个项目关注的是将这种反应推广到多种细胞类型， 提示PI 4P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的范例。项目2.该项目是 定义PLC信号在心力衰竭发展中的作用。我们已经证明，PLC删除可以防止 在体外和小鼠中发生肥大。在这里，我们专注于识别机械角色， PLC控制心脏细胞中调节心力衰竭的信号传导。项目3。我们开创了识别 调节GPCR下游的G蛋白激酶亚基信号传导的小分子， 这些分子具有潜在的治疗用途。在此，我们将进一步探讨 这些化合物，后续从使用这些化合物的结果，以确定新的G蛋白途径在细胞 迁移和识别用于治疗开发的新型化学支架。