HCMV US28 Signal Transduction by Betaarrestin proteins

Betaarrestin 蛋白的 HCMV US28 信号转导

基本信息

  • 批准号:
    7371077
  • 负责人:
  • 金额:
    $ 24.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2005
  • 资助国家:
    美国
  • 起止时间:
    2005-06-01 至 2010-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Human Cytomegalovirus (HCMV) infection is a leading cause of viral associated congenital birth defects and has proven to be a significant public health problem in organ transplant recipients as well as in individuals with AIDS. Accumulating evidence indicates that there may be a relationship between HCMV and the development of vascular disease. The interplay between HCMV and the immune system is a critical factor in the events leading to initiation of disease. Interestingly, HCMV encodes several genes that appear to modulate immune system function. One of these genes, termed US28, is homologous to the mammalian chemokine G-protein coupled receptors (GPCRs). While progress has recently been made in the identification of signaling pathways downstream of US28, very little is known regarding the molecular details proximal to US28 that contribute to the activation of signaling pathways. The objective of this proposal is to identify specific receptor properties and molecular events proximal to US28 that are critical for activation of known signal transduction pathways. We hypothesize that a detailed study of the molecular interactions of betaarrestin proteins with US28 will generate novel insights into the regulation of US28 signaling. The betaarrestins were originally identified in the context of termination of "traditional" G-protein signaling to effectors such as adenylyl cyclases and phospholipases. This termination process, also known as desensitization, involves receptor phosphorylation by GRKs and binding of betarrestin proteins. It is now clear that the betaarrestins simultaneously function as adapter/scaffold molecules to recruit signaling proteins to receptors in order to activate additional "non-traditional" signaling pathways. We have identified a US28 mutant that is unable to interact with betaarrestin and have generated a significant amount of preliminary data regarding signaling from this mutant. We propose to analyze the involvement of betaarrestin proteins in US28 signaling in order to gain a greater understanding of the proximal events leading to activation of US28 signaling pathways. To accomplish this goal, we propose three specific aims. First, we will characterize "traditional" signaling from this US28 mutant in the context of HCMV infection and will analyze how this mutant affects the ability of US28 to stimulate smooth muscle cell migration. Second, we will analyze "non-traditional" signaling pathways from US28 potentially mediated by betaarrestin recruitment to the US28 carboxy terminal regulatory domain. Third, we will analyze US28 signaling in cells deficient for betaarrestin expression in order to specifically define the involvement of betaarrestins. Our preliminary data indicate that US28 engages ?arrestin proteins suggesting that we will be able to make rapid progress toward our goal of defining the role of these important regulatory proteins in US28 signaling. These studies will identify mechanisms regulating US28 mediated signal transduction and will enhance our understanding of how US28 participates in pathogenesis and initiation of HCMV disease.
描述(由申请人提供):人巨细胞病毒(HCMV)感染是病毒相关先天性出生缺陷的主要原因,已被证明是器官移植受者以及艾滋病患者的重要公共卫生问题。越来越多的证据表明,HCMV与血管疾病的发生发展可能存在一定的关系。HCMV和免疫系统之间的相互作用是导致疾病发生的关键因素。有趣的是,HCMV编码几个似乎调节免疫系统功能的基因。这些基因之一,称为US 28,是同源的哺乳动物趋化因子G蛋白偶联受体(GPCR)。虽然最近在US 28下游信号通路的鉴定方面取得了进展,但关于US 28附近有助于信号通路激活的分子细节知之甚少。该提案的目的是确定特定的受体特性和分子事件近端的US 28是激活已知的信号转导途径的关键。我们假设,β抑制蛋白与US 28的分子相互作用的详细研究将产生新的见解US 28信号的调节。β抑制蛋白最初是在终止“传统”G蛋白信号传导至效应物如腺苷酸环化酶和磷脂酶的背景下鉴定的。该终止过程也称为脱敏,涉及GRKs的受体磷酸化和betarrestin蛋白的结合。现在清楚的是,β抑制蛋白同时作为衔接子/支架分子来募集信号蛋白到受体,以激活额外的“非传统”信号通路。我们已经鉴定了一种US 28突变体,其不能与β抑制蛋白相互作用,并且已经产生了大量关于来自该突变体的信号传导的初步数据。我们建议分析β抑制蛋白参与US 28信号转导,以获得更好的了解近端事件导致激活US 28信号通路。为了实现这一目标,我们提出了三个具体目标。首先,我们将表征HCMV感染背景下US 28突变体的“传统”信号传导,并分析该突变体如何影响US 28刺激平滑肌细胞迁移的能力。其次,我们将分析从US 28可能介导的β抑制蛋白募集到US 28羧基末端调控结构域的“非传统”信号通路。第三,我们将分析β抑制蛋白表达缺陷细胞中的US 28信号传导,以明确β抑制蛋白的参与。 我们的初步数据表明US 28参与了?抑制蛋白的研究表明,我们将能够朝着我们的目标取得快速进展,确定这些重要的调节蛋白在US 28信号传导中的作用。这些研究将确定调节US 28介导的信号转导的机制,并将增强我们对US 28如何参与HCMV疾病的发病机制和启动的理解。

项目成果

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WILLIAM E MILLER其他文献

WILLIAM E MILLER的其他文献

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{{ truncateString('WILLIAM E MILLER', 18)}}的其他基金

Investigation of the role of HDAC activity in regulation of HCMV replication in the salivary epithelium
HDAC 活性在调节唾液上皮 HCMV 复制中的作用的研究
  • 批准号:
    10739852
  • 财政年份:
    2023
  • 资助金额:
    $ 24.99万
  • 项目类别:
Mechanisms of vGPCR mediated Cytomegalovirus Growth in the Salivary Gland
vGPCR 介导巨细胞病毒在唾液腺中生长的机制
  • 批准号:
    10180884
  • 财政年份:
    2018
  • 资助金额:
    $ 24.99万
  • 项目类别:
Development of salisphere-derived systems for the study of cytomegalovirus vGPCR directed viral growth in the salivary gland
开发唾液球衍生系统用于研究巨细胞病毒 vGPCR 指导唾液腺中的病毒生长
  • 批准号:
    9317077
  • 财政年份:
    2017
  • 资助金额:
    $ 24.99万
  • 项目类别:
Mechanisms of vGPCR mediated Cytomegalovirus Growth in the Salivary Gland
vGPCR 介导巨细胞病毒在唾液腺中生长的机制
  • 批准号:
    9332531
  • 财政年份:
    2016
  • 资助金额:
    $ 24.99万
  • 项目类别:
Role of Cytomegalovirus GPCRs in Pathogenesis in Vivo
巨细胞病毒 GPCR 在体内发病机制中的作用
  • 批准号:
    8514752
  • 财政年份:
    2012
  • 资助金额:
    $ 24.99万
  • 项目类别:
HCMV US28 Signal Transduction by Betaarrestin proteins
Betaarrestin 蛋白的 HCMV US28 信号转导
  • 批准号:
    7068459
  • 财政年份:
    2005
  • 资助金额:
    $ 24.99万
  • 项目类别:
HCMV US28 Signal Transduction by Betaarrestin proteins
Betaarrestin 蛋白的 HCMV US28 信号转导
  • 批准号:
    6987737
  • 财政年份:
    2005
  • 资助金额:
    $ 24.99万
  • 项目类别:
HCMV US28 Signal Transduction by Betaarrestin proteins
Betaarrestin 蛋白的 HCMV US28 信号转导
  • 批准号:
    7188515
  • 财政年份:
    2005
  • 资助金额:
    $ 24.99万
  • 项目类别:
HCMV US28 Signal Transduction by Betaarrestin proteins
Betaarrestin 蛋白的 HCMV US28 信号转导
  • 批准号:
    7582343
  • 财政年份:
    2005
  • 资助金额:
    $ 24.99万
  • 项目类别:
Environmental Carcinogenesis and Mutagenesis
环境致癌和突变
  • 批准号:
    10189584
  • 财政年份:
    1988
  • 资助金额:
    $ 24.99万
  • 项目类别:

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