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

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
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-05-01 至 2023-04-30

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中文摘要
翻译
摘要 G蛋白偶联受体(GPCRs)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是治疗学的主要靶点。个体 GPCR直接与异源三聚体G蛋白和亚基的不同互补作用 下游信号通路塑造细胞反应,从而决定gpr的疗效。G和 G亚基直接与效应器相互作用,产生细胞反应。我们的实验室主要集中在 从BASIC分析谈G-亚单位信号和磷脂酶C信号 生化反应机制在确定疾病中的作用。在这项提案中,我们寻求将所有 将资助的实验室指示合并为一个提案。项目1。我们最近是第一个证明 磷脂酰肌醇4-磷酸是细胞内PLC活性的底物。这项最初的研究是在 心肌细胞。该项目致力于将这种反应推广到多种细胞类型,并提供了证据 提示PI4P是受体刺激的PLC信号的主要底物。这有可能改变 肌醇磷脂水解酶的受体依赖性调节范式。项目2.这个项目是为了 明确PLC信号在心力衰竭发展中的作用。我们已经展示了可编程控制器删除可防止 在体外和小鼠体内发生肥大。在这里,我们专注于确定以下方面的机械性角色 心肌细胞中调节心力衰竭的PLC信号。项目3.我们率先确定了 调节GPCRs下游G蛋白亚单位信号的小分子,并已表明 这些分子具有潜在的治疗作用。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 迁移和鉴定用于治疗开发的新型化学支架。
英文摘要
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.
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会议论文
Understanding and Manipulating G Protein α Subunit and Phospholipase C Signaling Networks
Understanding and Manipulating Phospholipase C and G Protein beta gamma subunit Signaling Networks
2015 Molecular Pharmacology Gordon Research Conference/Gordon Research Seminar
  • 批准号:
    8836740
  • 项目类别:
  • 资助金额:
    $2.5万
  • 财政年份:
    2015
  • 负责人:
    Alan V. Smrcka
  • 依托单位:
Phosphatidylinositol 4-Phosphate Hydrolysis in Spatiotemporal Cell Signaling
海外基金