Tyrosine Kinases in Autoimmunity

描述（由申请人提供）：免疫系统反应不适当的免疫性疾病，如一些过敏性和自身免疫性疾病，显示异常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ca2 +的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，我们认为对Itk的研究对我们了解这类免疫疾病很重要。我们提出Itk调节重要的TCR/ cd3诱导的信号转导事件，包括细胞内Ca++的动员和肌动蛋白细胞骨架的重组。此外，我们提出Itk通过其不同的结构域调节这些事件。鉴于这一假设，本建议将涉及以下三个具体目标：

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.