PKC-theta-induced NF-kB activation in T Cells

描述(申请人提供)：T淋巴细胞(T细胞)在免疫系统的调节中起着关键作用。T细胞的生理性增殖是通过与T细胞表面的T细胞受体(TCR)复合体结合来调节的。抗原结合的TCR复合体启动细胞内信号级联反应，激活多种转录因子，表达多种细胞因子，最终促进T细胞的增殖。T细胞中这些信号级联的放松将导致癌症，如白血病和淋巴瘤，或自身免疫性疾病，如关节炎和糖尿病。因此，揭示TCR信号级联的分子基础可能为设计治疗白血病和自身免疫性疾病的药物提供分子基础。本研究试图用分子和遗传学的方法来阐明TCR信号转导的分子机制。具体地说，我们将研究关键信号中间体PKC-theta是如何传递TCR信号来激活核因子-kappaB的，核因子-kappaB是一种主要的转录因子，控制着各种细胞因子、抗凋亡和炎症基因的表达。我们将确定包括Bcl10、CARD11、Paracaspase和PKD在内的信号分子是否为PKC-theta的下游靶标，并确定这些分子在TCR信号通路中的生物学作用。最后，为了研究TCR的信号转导，我们将利用体细胞遗传学并结合遗传互补的方法来确定TCR诱导的NF-kappaB激活所需的额外的未知信号成分。这些研究将提供关于TCR信号被传递到下游组件的分子机制的重要新信息，这些下游组件激活控制各种细胞因子和抗凋亡基因表达的核因子-kappaB家族。

DESCRIPTION (provided by applicant): 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.