Role of Carma1 in Inflammatory Lung Disease

Carma1 在炎症性肺病中的作用

基本信息

批准号：
7771637
负责人：
Benjamin David Medoff
金额：
$ 41.17万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7771637
关键词：
Address Antigens Asthma Backcrossings Biochemical Genetics Biology Cell physiology Chronic Disease Collection Complex Data Development Disease Experimental Designs Family Generations Genes Glucocorticoids Goals Health Host Defense Immune response Immunosuppressive Agents Infection Inflammation Inflammatory Lung Lung diseases Lymphocyte Mediating Mediator of activation protein Memory Modeling Molecular Mus Mutant Strains Mice Mutation Outcome Study Pathogenesis Pathway interactions Pharmaceutical Preparations Phosphorylation Phosphorylation Site Phosphotransferases Play Pneumonia Population Process Protein Fingerprints Proteins Proteomics Receptor Signaling Regulation Regulatory T-Lymphocyte Resolution Role Scaffolding Protein Serine Signal Pathway Signal Transduction Study Section T cell differentiation T memory cell T-Cell Activation T-Cell Development T-Cell Receptor T-Lymphocyte Testing Th2 Cells Transgenic Mice Transgenic Organisms airway inflammation allergic airway inflammation antigen challenge base candidate identification effective therapy immune function in vivo in vivo Model insight intermolecular interaction mouse model new therapeutic target novel promoter public health relevance transcription factor transmission process

项目摘要

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.

描述（由申请人提供）：NF-κB是一种转录因子，对于调节与炎症有关的许多基因的表达以及对于T细胞介导的炎症性疾病（例如哮喘）的发展至关重要。最近的研究表明，CARMA1-Bcl10-MALT1 信号通路对于 TCR 介导的 NF-κB 激活至关重要。与此相一致的是，我们已经证明 CARMA1 通过其在 T 淋巴细胞中的作用对于过敏性气道炎症的发生至关重要。此外，我们已经证明 CARMA1 依赖性信号传递是通过激酶的顺序磷酸化来调节的。然而，CARMA1 体内调节的确切机制仍不清楚。在四个相互关联的目标中，我们将探索 T 细胞中 CARMA1 的调节，并确定 Th2 型肺部炎症建立后 CARMA1 表达破坏的影响。实验设计强调使用肺部炎症体内模型以及基于生化和遗传学研究相互作用蛋白质分析的传统方法。这些研究的结果将深入了解健康和肺部炎症中的 NF-κB 信号传导，并可能确定新的治疗靶点。目标 1：表征小鼠哮喘模型中过敏性气道炎症发展过程中 CARMA1 在 T 淋巴细胞中的作用。目标 2：在小鼠哮喘模型中表征 CARMA1 在调节性 T 细胞 (Treg) 发育和功能中的作用。目标 3：通过转基因分析确定 CARMA1 丝氨酸磷酸化在淋巴细胞信号传导中的体内作用。目标 4：描绘 T 淋巴细胞中 CARMA1 激活的信号通路的新成分。公共卫生相关性。哮喘仍然是世界上最常见的慢性疾病之一。尽管使用糖皮质激素和免疫抑制剂可以实现有效的治疗，但这些药物会抑制广泛的免疫功能。在这项提案中，我们研究了一种与小鼠疾病模型中哮喘发展有关的蛋白质。从我们拟议的研究中获得的信息可能使我们能够针对这种疾病开发出更具体的治疗方法。