CARMA1-mediated NF-kB activation in lymphocyte activation

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T Lymphocyte (T cell) activation plays a critical role in immune responses. Deregulation of T cell activation will result in cancer, autoimmune, or immunodeficiency diseases. T cell activation is induced by majorhistocompatibility- complex (MHC) molecules on antigen-presenting cells (APC) presenting antigen peptides to T cell receptors (TCR) on the surface of T cells. This stimulation on TCR/CD3 complexes induces a series of signal transduction cascades leading to activation of multiple transcription factors including NF-kB, NF-AT, and AP-1. These transcription factors ultimately control the gene expression leading to production of cytokines and T cell proliferation. NF-kB is a family of transcription factors that play important roles in regulating the expression of various genes including cytokines, pro-survival factors, and inflammatory factors. Recent studies from our lab and others demonstrate that CARMA1, a scaffold molecule, plays an essential role in NF-kB activation following the stimulation of antigen receptors. Although it is clear that CARMA1 mediates antigen receptor-induced NF-kB activation through regulating IkB kinase (IKK) complex, the molecular mechanism by which CARMA1 is involved in IKK activation is not fully defined. To investigate how CARMA1 is involved in TCR-induced signal transduction, three specific aims are proposed in this application. The specific aims are: (1) to determine how CARMA1 is involved in activation of IKK complex; (2) to determine how antigen receptor signaling pathway regulates CARMA1; (3) to determine how CARMA1 is recruited into the immunological synapse. These studies will not only reveal the basic mechanism of the TCR-induced signaling pathway, but also provide the molecular insight for determining the unknown causes of autoimmunity, immunodeficiency, and cellular malignancy in leukemia and lymphoma. Therefore, the results from these studies may provide the molecular basis for designing novel therapeutic agents to treat these diseases.