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.

Public Health Relevance

The use of gene therapy to enhance the expression of therapeutic genes shows great promise for future therapy in the heart, however, several hurdles remain. In this application, we will examine the newest generation of viral delivery vectors to enhance the delivery of these therapeutic proteins and to examine the mechanisms responsible for the cardioprotective effects. Moreover, we will take a major step towards translation of these findings into the clinical setting by examining their application in a porcine model.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072010-09
Application #
8251201
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wong, Renee P
Project Start
2003-05-02
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$588,165
Indirect Cost
$211,136
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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; Gomez, Jose A; Payne, Alan J et al. (2014) Abi3bp regulates cardiac progenitor cell proliferation and differentiation. Circ Res 115:1007-16
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
Beigi, Farideh; Schmeckpeper, Jeffrey; Pow-Anpongkul, Pete et al. (2013) C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway. Circ Res 113:372-80
Wang, Hao; Gomez, Jose A; Klein, Sabine et al. (2013) Adult renal mesenchymal stem cell-like cells contribute to juxtaglomerular cell recruitment. J Am Soc Nephrol 24:1263-73
Jayawardena, Tilanthi M; Egemnazarov, Bakytbek; Finch, Elizabeth A et al. (2012) MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res 110:1465-73
Mirotsou, Maria; Jayawardena, Tilanthi M; Schmeckpeper, Jeffrey et al. (2011) Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol 50:280-9
Hodgkinson, Conrad P; Gomez, José A; Mirotsou, Maria et al. (2010) Genetic engineering of mesenchymal stem cells and its application in human disease therapy. Hum Gene Ther 21:1513-26
Huang, Jing; Zhang, Zhiping; Guo, Jian et al. (2010) Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circ Res 106:1753-62
Matsushita, Kenichi; Morello, Fulvio; Wu, Yaojiong et al. (2010) Mesenchymal stem cells differentiate into renin-producing juxtaglomerular (JG)-like cells under the control of liver X receptor-alpha. J Biol Chem 285:11974-82

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