T lymphocytes (T cell) play critical roles in regulation of immune system. The physiological expansion of T cells is regulated by binding of specific antigens to T cell receptor (TCR) complexes on the surfaces of T cells. The antigen-bound TCR complexes initiate intracellular signaling cascades, which lead to activation of multiple transcription factors and expression of various cytokines, and ultimately promote proliferation of T cells. Deregulation of these signaling cascades in T cells will result in cancers such as leukemia and lymphoma, or autoimmune diseases such as arthritis and diabetes. Therefore, revealing the molecular basis of TCR signaling cascades may provide molecular insight for designing therapeutic agents to treat patients of leukemia and autoimmune diseases. The present proposal seeks to apply molecular and genetic approaches to elucidate molecular mechanism of TCR signal transduction. Specifically, we will investigate how PKC-theta, a key signaling intermediate, transmits TCR signals to activate NF-kappaB, a major transcription factor that controls the expression of various cytokines, anti-apoptotic and inflammatory genes. We will determine whether signaling molecules including Bcl10, CARD11, Paracaspase, and PKD are downstream targets of PKC-theta and determine the biological roles of these molecules in the TCR signaling pathway. Finally, to study TCR signal transduction, we will use somatic genetics and combine with genetic complementation approaches to identify additional, unknown signaling components that are required for the TCR-induced NF-kappaB activation. These studies will provide essential new information about the molecular mechanisms by which TCR signals are transmitted to downstream components that activate the NF-kappaB family of transcription factors controlling expression of various cytokines and antiapoptotic genes.
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