Decline in the immune system is a feature of human aging. Reduction in naive T cell repertoire to combat novel pathogens stems from decreased function of the thymus where T cells develop. Stage-specific signal transduction and gene expression, resulting from reciprocal cell-cell interactions and locally produced cytokines and hormones, is critical for T cell development. Cues from stromal cells regulate an exquisite balance of proliferation, quiescence, cell-death and cell-fate decisions in developing thymocytes. In turn, thymocytes regulate the maturation of thymic epithelial cells. Understanding this interplay at a molecular level will provide insights that might be translated into novel therapies. We have found that transgenic mice expressing beta-catenin CAT-Tg mice exhibit accelerated age-dependent thymic involution and aging. The mechanistic basis for beta-catenin-mediated thymic involution remains a major focus of our laboratory. The long-term goal of our research is to delineate molecular interactions that significantly regulate T cell development in the thymus with the aim of further defining these processes and establish protocols to boost thymic function in the elderly and immunocompromised subjects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000768-10
Application #
8736621
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2013
Total Cost
$114,071
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Berga-Bolaños, Rosa; Sharma, Archna; Steinke, Farrah C et al. (2015) β-Catenin is required for the differentiation of iNKT2 and iNKT17 cells that augment IL-25-dependent lung inflammation. BMC Immunol 16:62
Prevot, Nicolas; Pyaram, Kalyani; Bischoff, Evan et al. (2015) Mammalian target of rapamycin complex 2 regulates invariant NKT cell development and function independent of promyelocytic leukemia zinc-finger. J Immunol 194:223-30
Wu, Tuoqi; Shin, Hyun Mu; Moseman, E Ashley et al. (2015) TCF1 Is Required for the T Follicular Helper Cell Response to Viral Infection. Cell Rep 12:2099-110
Berga-Bolaños, Rosa; Zhu, Wandi S; Steinke, Farrah C et al. (2015) Cell-autonomous requirement for TCF1 and LEF1 in the development of Natural Killer T cells. Mol Immunol 68:484-9
Sharma, A; Sen, J M (2013) Molecular basis for the tissue specificity of β-catenin oncogenesis. Oncogene 32:1901-9
Ait-Ali, Djida; Stroth, Nikolas; Sen, Jyoti M et al. (2010) PACAP-cytokine interactions govern adrenal neuropeptide biosynthesis after systemic administration of LPS. Neuropharmacology 58:208-14
Yu, Qing; Sharma, Archna; Sen, Jyoti Misra (2010) TCF1 and beta-catenin regulate T cell development and function. Immunol Res 47:45-55
Xu, Mai; Sharma, Archna; Hossain, M Zulfiquer et al. (2009) Sustained expression of pre-TCR induced beta-catenin in post-beta-selection thymocytes blocks T cell development. J Immunol 182:759-65
Xu, Mai; Sharma, Archna; Wiest, David L et al. (2009) Pre-TCR-induced beta-catenin facilitates traversal through beta-selection. J Immunol 182:751-8
Yu, Qing; Quinn 3rd, William J; Salay, Theresa et al. (2008) Role of beta-catenin in B cell development and function. J Immunol 181:3777-83

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