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Tyrosine Kinases in Autoimmunity

自身免疫中的酪氨酸激酶

基本信息

批准号：
7197330
负责人：
CONSTANTINE D TSOUKAS
金额：
$ 25.2万
依托单位：
SAN DIEGO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-09 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7197330
关键词：
Actins Address Allergic Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antibody Formation Autoimmune Diseases Autoimmune Process Autoimmunity Cytoskeleton Data Event Experimental Models Extrinsic asthma Guanine Nucleotide Exchange Factors Hypersensitivity Immune System Diseases Immune system Inflammatory Jurkat Cells Laboratories Lung Mediating Monomeric GTP-Binding Proteins Mus Nucleotides Pathology Pathway interactions Patients Phenotype Phosphorylation Phosphotransferases Play Production Protein Tyrosine Kinase Proteins Regulation Role Signal Pathway Signal Transduction Signal Transduction Pathway System Systemic Lupus Erythematosus T-Cell Development T-Cell Proliferation T-Cell Receptor T-Lymphocyte Testing Transcriptional Activation Transgenes Transgenic Animals Transgenic Mice Tyrosine Phosphorylation Virus Diseases cytokine human disease in vivo interest mutant pathogen polymerization reconstitution response transgene expression vasodilator-stimulated phosphoprotein

项目摘要

DESCRIPTION (provided by applicant): Immunological diseases where the immune system responds inappropriately, such as some allergic and autoimmune disorders, display aberrant T cell antigen receptor (TCR/CD3)-induced signaling events. These may include intracellular Ca++ mobilization and the reorganization of the actin cytoskeleton. The protein tyrosine kinase Itk is a critical regulator of these events. Therefore, we believe studies on Itk are important to our understanding of such immunological diseases. We propose the hypothesis that Itk regulates important TCR/CD3-induced signal transduction events including intracellular Ca++ mobilization and reorganization of the actin cytoskeleton. Furthermore, we propose that Itk regulates these events through its various structural domains. In view of this hypothesis the present proposal will address the following three specific aims: 1) Structural requirements of Itk on T cell development and activation. We will reconstitute Itk-deficient mice with selected mutant Itk transgenes that have been shown to display interesting phenotypes. Reconstituted mice will be tested for effects on T cell development, activation, transcriptional activation and cytokine production, TCR-proximal signaling events, and in vivo responses to viral infection. 2) Structural requirements of Itk on the modulation of allergic asthma. For these studies we will utilize the Itk transgenic mice of specific aim 1. Reconstituted mice will be challenged in an experimental model of allergic asthma and the effects of various Itk transgene expression on lung pathology, T cell proliferation, and cytokine production will be determined. 3) Involvement of Itk in TCR/CD3-induced cytoskeletal events. We will assess the involvement of Itk on TCR/CD3-induced actin polymerization, the inducible interaction of Itk with WASP, the interaction of WASP with other actin-polymerization related proteins (e.g. VASP and Arp2/3), and the Ilk structural requirements for these interactions, the role of the Itk-mediated phosphorylation of WASP on actin polymerization, and the involvement of Itk in TCR/CD3-mediated activation of small GTPases and the nucleotide exchange factor Vav.

描述（由申请人提供）：免疫系统反应不当的免疫疾病，例如一些过敏性和自身免疫性疾病，表现出异常的 T 细胞抗原受体 (TCR/CD3) 诱导的信号事件。这些可能包括细胞内 Ca++ 动员和肌动蛋白细胞骨架的重组。蛋白酪氨酸激酶 Itk 是这些事件的关键调节因子。因此，我们相信对 Itk 的研究对于我们了解此类免疫疾病非常重要。我们提出这样的假设：Itk 调节重要的 TCR/CD3 诱导的信号转导事件，包括细胞内 Ca++ 动员和肌动蛋白细胞骨架的重组。此外，我们建议 Itk 通过其各种结构域来调节这些事件。鉴于这一假设，本提案将解决以下三个具体目标： 1) Itk对T细胞发育和激活的结构要求。我们将用选定的突变型 Itk 转基因重建 Itk 缺陷小鼠，这些突变型 Itk 转基因已被证明表现出有趣的表型。将测试重组小鼠对 T 细胞发育、激活、转录激活和细胞因子产生、TCR 近端信号传导事件以及对病毒感染的体内反应的影响。 2) Itk对调节过敏性哮喘的结构要求。对于这些研究，我们将利用特定目标 1 的 Itk 转基因小鼠。将在过敏性哮喘实验模型中挑战重组小鼠，并确定各种 Itk 转基因表达对肺病理学、T 细胞增殖和细胞因子产生的影响。 3) Itk 参与 TCR/CD3 诱导的细胞骨架事件。我们将评估 Itk 对 TCR/CD3 诱导的肌动蛋白聚合的参与，Itk 与 WASP 的诱导相互作用，WASP 与其他肌动蛋白聚合相关蛋白（例如 VASP 和 Arp2/3）的相互作用，以及这些相互作用的 Ilk 结构要求，Itk 介导的 WASP 磷酸化对肌动蛋白聚合的作用，以及 Itk 的参与 TCR/CD3 介导的小 GTP 酶和核苷酸交换因子 Vav 的激活。