Role of Carma1 in Inflammatory Lung Disease

描述(申请人提供)：核因子？B是一种转录因子，对调节许多参与炎症的基因的表达至关重要，并对T细胞介导的炎症性疾病(如哮喘)的发展至关重要。最近的研究表明，CARMA1-Bcl10-MALT1信号通路在TCR介导的NF-B活化中起着至关重要的作用。与此一致，我们已经证明了CARMA1通过其在T淋巴细胞中的作用在过敏性呼吸道炎症的发展中是必不可少的。此外，我们还发现，依赖于CARMA1的信号传递受蛋白激酶的顺序磷酸化调控。然而，CARMA1在体内调节的确切机制仍然不清楚。在四个相互关联的目标中，我们将探索CARMA1在T细胞中的调节，并确定在Th2型肺炎症建立后CARMA1表达中断的效果。实验设计强调使用肺部炎症的活体模型，以及基于生化和遗传学研究相互作用蛋白分析的传统方法。这些研究的结果将为深入了解核因子-βB信号在健康和肺部炎症中的作用提供依据，并可能确定新的治疗靶点。目的：探讨CARMA1在哮喘小鼠过敏性气道炎症中的作用。目的：研究CARMA1在哮喘小鼠模型调节性T细胞(Treg)发育和功能中的作用。目的：通过转基因分析确定CARMA1丝氨酸磷酸化在体内对淋巴细胞信号转导的作用。目的4：研究CARMA1激活T淋巴细胞信号转导途径的新成分。与公共卫生相关。哮喘仍然是世界上最常见的慢性病之一。虽然有效的治疗是通过使用糖皮质激素和免疫抑制剂来实现的，但这些药物抑制了广泛的免疫功能。在这项建议中，我们研究了一种在小鼠疾病模型中参与哮喘发展的蛋白质。从我们提议的研究中获得的信息可能会让我们开发出更具体的治疗这种疾病的方法。

DESCRIPTION (provided by applicant): NF-?B is a transcription factor crucial for regulating the expression of many genes involved in inflammation, and for the development of T cell-mediated inflammatory diseases such as asthma. Recent studies have demonstrated that the CARMA1-Bcl10- MALT1 signaling pathway is essential for TCR mediated NF-?B activation. Consistent with this, we have demonstrated that CARMA1 is essential for the development of allergic airway inflammation through its role in T lymphocytes. Furthermore, we have shown that CARMA1 dependent signal transmission is regulated by sequential phosphorylation by kinases. However, the exact mechanism of CARMA1 regulation in vivo remains elusive. In four interrelated aims, we will explore the regulation of CARMA1 in T cells and determine the effect of disruption of CARMA1 expression after the establishment of Th2-type pulmonary inflammation. The experimental design emphasizes the use of in vivo models of pulmonary inflammation as well as conventional approaches based on the analysis of interacting proteins using biochemical and genetic studies. The outcome of these studies will provide insight into NF-?B signaling in health and pulmonary inflammation, and may identify novel therapeutic targets. Aim 1: To characterize the role of CARMA1 in T lymphocytes during the development of allergic airway inflammation in a murine model of asthma. Aim 2: To characterize the role of CARMA1 in regulatory T cell (Treg) development and function in a murine model of asthma. Aim 3: To determine the in vivo role of serine phosphorylation of CARMA1 in lymphocyte signaling by transgenic analysis. Aim 4: To delineate novel components of signaling pathways activated by CARMA1 in T lymphocytes. PUBLIC HEALTH RELEVANCE. Asthma remains one of the most common chronic diseases in the world. Although effective therapy is achieved by the use of glucocorticoids and immunosuppressants, these drugs suppress a broad spectrum of immune function. In this proposal we investigate a protein involved in the development of asthma in a mouse model of disease. The information obtained from our proposed studies may allow us to develop more specific therapy for this disorder.