Abstract

The nuclear hormone receptor superfamily is composed of ligand-regulated transcription factors and orphan receptors, for which ligands are not identified or may not exist. These receptors perform extremely diverse functions in development, reproduction, and homeostasis by regulating cell growth, differentiation, and apoptosis. Aberrant activities of some hormone receptors have been causally linked to neoplasia. Recently, studies from our group and others on the orphan nuclear receptors ROR-gamma (Retinoic acid receptor-related Orphan Receptor) and its thymus specific isoform ROR-gamma-t demonstrated that this nuclear receptor regulates the survival and cell cycle status of CD4+CD8+ double-positive thymocyte. However, the role of ROR-gamma-t/ROR-gamma in thymocyte differentiation remains largely unknown. In this proposal, we will perform experiments to determine how ROR-gamma-t/ROR-gamma regulates thymocyte positive and negative selection through the use of animals lacking ROR-gamma-t/ROR-gamma expression. Furthermore, we will examine the regulation of pre-TCRa by ROR-gamma-t in vivo. These experiments will provide important new information regarding the role of ROR-gamma-t and ROR-gamma in thymopoiesis and the molecular basis of thymocyte differentiation. In addition, results from this application will also provide insights for the role of ROR-gamma-t in tumorigenesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092123-04
Application #
6925477
Study Section
Immunobiology Study Section (IMB)
Program Officer
Mccarthy, Susan A
Project Start
2002-08-28
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
4
Fiscal Year
2005
Total Cost
$308,385
Indirect Cost

  Institution

Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Dunkle, Alexis; He, You-Wen (2011) Apoptosis and autophagy in the regulation of T lymphocyte function. Immunol Res 49:70-86
Tilson, Julie K; Sullivan, Katherine J; Cen, Steven Y et al. (2010) Meaningful gait speed improvement during the first 60 days poststroke: minimal clinically important difference. Phys Ther 90:196-208
Gordy, Claire; Dzhagalov, Ivan; He, You-Wen (2009) Regulation of CD8(+) T cell functions by RARgamma. Semin Immunol 21:2-7
Zhang, Nu; Hopkins, Kaycie; He, You-Wen (2008) c-FLIP protects mature T lymphocytes from TCR-mediated killing. J Immunol 181:5368-73
Dzhagalov, Ivan; Dunkle, Alexis; He, You-Wen (2008) The anti-apoptotic Bcl-2 family member Mcl-1 promotes T lymphocyte survival at multiple stages. J Immunol 181:521-8
Zhang, Nu; Hopkins, Kaycie; He, You-Wen (2008) The long isoform of cellular FLIP is essential for T lymphocyte proliferation through an NF-kappaB-independent pathway. J Immunol 180:5506-11
Gu, Jing Jin; Zhang, Nu; He, You-Wen et al. (2007) Defective T cell development and function in the absence of Abelson kinases. J Immunol 179:7334-43
Dzhagalov, Ivan; St John, Ashley; He, You-Wen (2007) The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages. Blood 109:1620-6
Pua, Heather H; Dzhagalov, Ivan; Chuck, Mariana et al. (2007) A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med 204:25-31
Dzhagalov, Ivan; Chambon, Pierre; He, You-Wen (2007) Regulation of CD8+ T lymphocyte effector function and macrophage inflammatory cytokine production by retinoic acid receptor gamma. J Immunol 178:2113-21

Showing the most recent 10 out of 19 publications