Role of Carma1 in Inflammatory Lung Disease

Massachusetts General Hospital, Boston MA

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Abstract

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.