This application addresses broad Challenge Area (11): Regenerative Medicine, and specific Challenge Topic 11-HL-101: Develop cell-based therapies for cardiovascular, lung, and blood diseases. Regenerative medicine holds the potential to repair and regenerate many tissues previous thought to be irretrievably lost due to acute damage or chronic stress damage including the heart. At present the primary barriers to efficient tissue repair in the myocardium by cardiac stem cells (CSCs) are cellular survival and proliferative capacity. This proposal will enhance cardiac myogenesis by improving survival and replicative capacity of adoptively transferred CSCs via genetic engineering with a cardioprotective kinase known as Pim-1. CSCs modified to express Pim-1 kinase will exhibit enhanced replication and de novo myocardium formation of in hearts of infarcted mice. Accomplishing the stated aims supports the long term goal to advance findings toward translational therapeutic implementation of ex vivo gene therapy to enhance stem cell-based cardiac repair. The short term goal is to validate, optimize, and understand the mechanistic basis for CSC-mediated myogenesis.
Specific aims are: 1) Assess long term persistence characteristics of Pim-1 engineered stem cells in promotion of myocardial repair and regeneration;2) Enhance the regenerative potential of human CSCs by Pim-1 overexpression using ex vivo gene therapy;and 3) Develop novel imaging strategies to determine the fate of engrafted CPCs and improve our understanding of stem cell biology in vivo. The significance of these studies is dramatic enhancement of stem cell-mediated myogenesis resulting in profound potentiation of regeneration, thereby offering marked improvements in cardiac structure and function superior to outcomes of current treatment modalities. The combination of studies in this project will unify the Pim-1 genetic engineering approach with novel imaging to track adoptively transferred cells in vivo. Collectively, these studies will provide a comprehensive picture of myogenesis and myocardial regeneration mediated by regular CSCs as well as those engineered to express Pim-1 and will produce fundamental results that will be critical for moving from the experimental setting into clinical implementation.
Heart disease remains a major cause or morbidity and mortality in the United States, with long term care and hospitalization of patients a significant burden on the national health care system. Despite advances over the last several decades we are still not truly capable of addressing the fundamental issue in heart failure: the progressive loss of contractile function and viable tissue. This proposal is focused on fundamental molecular mechanisms of survival and repair to enhance recovery of myocardial function after pathologic injury.
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| Khan, Mohsin; Mohsin, Sadia; Toko, Haruhiro et al. (2014) Cardiac progenitor cells engineered with ?ARKct have enhanced ?-adrenergic tolerance. Mol Ther 22:178-85 |
| Konstandin, Mathias H; Toko, Haruhiro; Gastelum, Grady M et al. (2013) Fibronectin is essential for reparative cardiac progenitor cell response after myocardial infarction. Circ Res 113:115-25 |
| Toko, Haruhiro; Konstandin, Mathias H; Doroudgar, Shirin et al. (2013) Regulation of cardiac hypertrophic signaling by prolyl isomerase Pin1. Circ Res 112:1244-52 |
| Konstandin, Mathias H; Völkers, Mirko; Collins, Brett et al. (2013) Fibronectin contributes to pathological cardiac hypertrophy but not physiological growth. Basic Res Cardiol 108:375 |
| Din, Shabana; Mason, Matthew; Völkers, Mirko et al. (2013) Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation. Proc Natl Acad Sci U S A 110:5969-74 |
| Siddiqi, Sailay; Sussman, Mark A (2013) Cell and gene therapy for severe heart failure patients: the time and place for Pim-1 kinase. Expert Rev Cardiovasc Ther 11:949-57 |
| Khan, Mohsin; Mohsin, Sadia; Avitabile, Daniele et al. (2013) ?-Adrenergic regulation of cardiac progenitor cell death versus survival and proliferation. Circ Res 112:476-86 |
| Bailey, Brandi; Fransioli, Jenna; Gude, Natalie A et al. (2012) Sca-1 knockout impairs myocardial and cardiac progenitor cell function. Circ Res 111:750-60 |
| Gude, Natalie; Sussman, Mark (2012) Notch signaling and cardiac repair. J Mol Cell Cardiol 52:1226-32 |
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