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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI053147-03
Application #
7068082
Study Section
Immunobiology Study Section (IMB)
Program Officer
Winter, David B
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$336,183
Indirect Cost
Name
University of Illinois at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
He, Zhiheng; Wang, Fei; Zhang, Jing et al. (2017) Regulation of Th17 Differentiation by IKK?-Dependent and -Independent Phosphorylation of ROR?t. J Immunol 199:955-964
He, Zhiheng; Ma, Jian; Wang, Ruiqing et al. (2017) A two-amino-acid substitution in the transcription factor ROR?t disrupts its function in TH17 differentiation but not in thymocyte development. Nat Immunol 18:1128-1138
He, Zhiheng; Wang, Fei; Ma, Jian et al. (2016) Ubiquitination of ROR?t at Lysine 446 Limits Th17 Differentiation by Controlling Coactivator Recruitment. J Immunol 197:1148-58
Kwon, Myung-Ja; Ma, Jian; Ding, Yan et al. (2012) Protein kinase C-? promotes Th17 differentiation via upregulation of Stat3. J Immunol 188:5887-97
Ma, Jian; Wang, Ruiqing; Fang, Xianfeng et al. (2012) ?-catenin/TCF-1 pathway in T cell development and differentiation. J Neuroimmune Pharmacol 7:750-62
Sun, Zuoming (2012) Intervention of PKC-? as an immunosuppressive regimen. Front Immunol 3:225
Ma, Jian; Ding, Yan; Fang, Xianfeng et al. (2012) Protein kinase C-? inhibits inducible regulatory T cell differentiation via an AKT-Foxo1/3a-dependent pathway. J Immunol 188:5337-47
Fang, Xianfeng; Wang, Ruiqing; Ma, Jian et al. (2012) Ameliorated ConA-induced hepatitis in the absence of PKC-theta. PLoS One 7:e31174
Wang, Ruiqing; Xie, Huimin; Huang, Zhaofeng et al. (2011) Transcription factor network regulating CD(+)CD8(+) thymocyte survival. Crit Rev Immunol 31:447-58
Ma, Jian; Wang, Ruiqing; Fang, Xianfeng et al. (2011) Critical role of TCF-1 in repression of the IL-17 gene. PLoS One 6:e24768

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