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：
7466234
负责人：
Benjamin David Medoff
金额：
$ 40.86万
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/7466234
关键词：
Address Antigens Asthma Backcrossings Biochemical Genetics Biology Cell Differentiation process Cell physiology Chronic Disease Collection Complex Data Development Disease Disruption 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 Public Health Receptor Signaling Regulation Resolution Role Scaffolding Protein Serine Signal Pathway Signal Transduction Study Section 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 immune function in vivo in vivo Model insight intermolecular interaction mouse model novel novel therapeutics promoter therapeutic target 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-？b对于调节许多涉及炎症基因的表达以及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信号通路对于TCR介导的NF-？B激活至关重要。与此一致，我们已经证明CARMA1通过其在T淋巴细胞中的作用而对过敏性气道炎症的发展至关重要。此外，我们已经表明，CARMA1依赖性信号传递受激酶的顺序磷酸化调节。然而，体内CARMA1调节的确切机制仍然难以捉摸。在四个相互关联的目标中，我们将探索T细胞中Carma1的调节，并确定建立Th2型肺部炎症后CARMA1表达的破坏作用。实验设计强调了基于生化和遗传研究对相互作用蛋白的分析，使用肺部炎症的体内模型以及常规方法。这些研究的结果将为健康和肺部炎症中的NF-信号传导提供洞察力，并可以鉴定出新的治疗靶标。目标1：表征Carma1在哮喘的鼠模型中过敏性气道炎症过程中T淋巴细胞中的作用。目标2：表征Carma1在哮喘的鼠模型中Carma1在调节性T细胞（TREG）发育和功能中的作用。 AIM 3：通过转基因分析确定Carma1的丝氨酸磷酸化在淋巴细胞信号中的体内作用。 AIM 4：描绘由Carma1在T淋巴细胞中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。尽管通过使用糖皮质激素和免疫抑制剂来实现有效的治疗，但这些药物抑制了广泛的免疫功能。在此提案中，我们研究了一种参与疾病小鼠模型中哮喘发展的蛋白质。从我们提出的研究中获得的信息可能使我们能够为这种疾病开发更具体的疗法。