Regulated apoptosis is critical to T cell development in the thymus and controls T cell- dependent adaptive immunity in periphery. 2-catenin, a coactivator of T cell factor 1 (TCF-1), and retinoid-related orphan receptor gamma t (ROR3t) both regulate thymocyte survival via the up-regulation of anti-apoptotic Bcl-xL. In the process of studying ROR3t, we have identified 2- catenin/TCF-1 as a potential upstream pathway that controls ROR3t-mediated thymocyte survival. Deletion of TCF-1 resulted in thymocyte apoptosis and down-regulated ROR3t, whereas transgenic expression of a stabilized 2-catenin (2-catTg), which activated TCF-1 constitutively, led to enhanced thymocyte survival and up-regulated ROR3t. In contrast to its survival role in thymocytes, 2-catTg up-regulated pro-apoptotic Bid and surface Fas, and enhanced super-antigen staphylococcal enterotoxin B (SEB)-induced deletion of peripheral T cells by promoting activation-induced cell death (AICD). We thus hypothesize that the 2- catenin/TCF pathway utilizes distinct mechanisms in the regulation of apoptosis in developing T cells and peripheral mature T cells. In the first two aims of this study, we propose to elucidate the mechanisms responsible for 2-catenin/TCF-1-regulated apoptosis in thymocytes and peripheral T cells. In the last aim, we will determine whether we can control T cell-dependent allograft rejection by manipulating 2-catenin-regulated T cell survival. Public Health Relevance: This proposal is to study the mechanisms responsible for 2-catenin and ROR3t-regulated T cell apoptosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wong, Renee P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Li, Yanzhen; Dal-Pra, Sophie; Mirotsou, Maria et al. (2016) Tissue-engineered 3-dimensional (3D) microenvironment enhances the direct reprogramming of fibroblasts into cardiomyocytes by microRNAs. Sci Rep 6:38815
Yuan, Hsiangkuo; Gomez, Jose A; Chien, Jennifer S et al. (2016) Tracking mesenchymal stromal cells using an ultra-bright TAT-functionalized plasmonic-active nanoplatform. J Biophotonics 9:406-13
Hodgkinson, Conrad P; Bareja, Akshay; Gomez, José A et al. (2016) Emerging Concepts in Paracrine Mechanisms in Regenerative Cardiovascular Medicine and Biology. Circ Res 118:95-107
Matsushita, Kenichi; Wu, Yaojiong; Pratt, Richard E et al. (2016) Deletion of angiotensin II type 2 receptor accelerates adipogenesis in murine mesenchymal stem cells via Wnt10b/beta-catenin signaling. Lab Invest 96:909-17
Matsushita, Kenichi; Morello, Fulvio; Zhang, Zhiping et al. (2016) Nuclear hormone receptor LXRα inhibits adipocyte differentiation of mesenchymal stem cells with Wnt/beta-catenin signaling. Lab Invest 96:230-8
Jayawardena, Tilanthi M; Finch, Elizabeth A; Zhang, Lunan et al. (2015) MicroRNA induced cardiac reprogramming in vivo: evidence for mature cardiac myocytes and improved cardiac function. Circ Res 116:418-24
Hodgkinson, Conrad P; Kang, Martin H; Dal-Pra, Sophie et al. (2015) MicroRNAs and Cardiac Regeneration. Circ Res 116:1700-11
Schmeckpeper, Jeffrey; Verma, Amanda; Yin, Lucy et al. (2015) Inhibition of Wnt6 by Sfrp2 regulates adult cardiac progenitor cell differentiation by differential modulation of Wnt pathways. J Mol Cell Cardiol 85:215-25
Yang, Yanqiang; Gomez, Jose A; Herrera, Marcela et al. (2015) Salt restriction leads to activation of adult renal mesenchymal stromal cell-like cells via prostaglandin E2 and E-prostanoid receptor 4. Hypertension 65:1047-54
Huang, Jing; Guo, Jian; Beigi, Farideh et al. (2014) HASF is a stem cell paracrine factor that activates PKC epsilon mediated cytoprotection. J Mol Cell Cardiol 66:157-64

Showing the most recent 10 out of 48 publications