In vivo Analysis of RORgamma mediated Functions

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DESCRIPTION (provided by applicant): Apoptosis is an essential physiological process required for the development and maintenance of homeostasis in an organism. The Bcl-2 proto-oncogene is a critical regulator of the apoptotic signaling pathways. Altered expression of Bcl-2 contributes to cancer pathogenesis and resistance to chemotherapeutic drugs due to failed induction of apoptosis. Apoptosis serves to eliminate majority of the developing thymocytes that are either not recognized by major histocompatibility complexes or self-reactive. By gene targeting, we have demonstrated that retinoid-related orphan receptor gamma (RORgamma), a member of the nuclear receptor family, plays a critical role in the development of thymocytes and lymph nodes. In the absence of RORgamma, thymocytes undergo rapid apoptosis and unregulated entry into S phase of the cell cycle. Correspondingly, RORgamma deficient thymocytes have significant lower levels of anti-apoptotic Bcl-xL and cell cycle inhibitor p27kip1. Overexpression of Bcl-xL in the RORgamma deficient thymocytes restores survival and cell cycle progression. RORgamma null mice fail to develop lymph nodes, likely due to absence of lymph node progenitors in the early embryonic stages. We hypothesize that RORgamma regulates expression of the critical survival and cell cycle molecules that are required for the development of thymocytes and lymph nodes. We propose to study the molecular mechanisms responsible for RORgamma mediated transcription and its function in thymocyte maturation in vivo. In addition, we will examine how RORgamma regulates the development of peripheral lymphoid organs. The proposed studies will gain insight into nuclear receptor regulated functions in development of T cells and the secondary lymphoid tissues in vivo.