Role of Carma1 in Inflammatory Lung Disease

Carma1 在炎症性肺病中的作用

• 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
• 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

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（申请人提供）：NF-？B是一种转录因子，对调节炎症中涉及的许多基因的表达以及T细胞介导的炎性疾病如哮喘的发展至关重要。最近的研究表明，CARMA 1-Bcl 10-MALT 1信号通路是TCR介导的NF-？B激活。与此一致，我们已经证明CARMA 1通过其在T淋巴细胞中的作用对过敏性气道炎症的发展至关重要。此外，我们已经表明，CARMA 1依赖性信号传递是由激酶的顺序磷酸化调节的。然而，体内CARMA 1调控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CARMA 1的调节，并确定在Th 2型肺部炎症建立后CARMA 1表达中断的影响。实验设计强调使用肺部炎症的体内模型以及基于使用生化和遗传研究分析相互作用蛋白的常规方法。这些研究的结果将提供深入了解NF-？B信号在健康和肺部炎症，并可能确定新的治疗靶点。目的1：研究CARMA 1在哮喘小鼠气道变应性炎症发生发展中的作用。目的2：研究CARMA 1在哮喘小鼠模型中调节性T细胞（Treg）发育和功能中的作用。目的3：通过转基因分析确定CARMA 1丝氨酸磷酸化在淋巴细胞信号传导中的体内作用。目的4：描述CARMA 1在T淋巴细胞中激活的信号通路的新组分。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。虽然有效的治疗是通过使用糖皮质激素和免疫抑制剂，这些药物抑制了广泛的免疫功能。在这个建议中，我们研究了一种蛋白质参与哮喘的发展，在小鼠模型的疾病。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治疗方法。