This is a competitive renewal application of a project initially designed to define mechanisms of cardiac myocyte dysfunction that leads to heart failure, a significant health problem in the US. Work in previous funding cycles has shown that cardiac diseases cause abnormalities in intracellular Calcium regulation and myocyte contractility. These abnormalities lead to cell death, and reduction in the number of functional cardiac myocytes. The major goal of the proposed research is to test/develop novel cell-based approaches to repair the heart after myocardial infarction (MI). The idea is that cardiac structura and functional decline after MI can be reduced or corrected using cell therapy.
The Aims are to 1) Determine if/how enhancing Cn43 expression in cardiac (CSC) or compact bone derived stem cells (CBSCs) enhances their survival, engraftment and differentiation into new cardiac tissue when injected into the infarct border zone after MI~ thus increasing their capacity to improve post-MI cardiac structure and function~ and 2) Determine the role of ?1G T-type Ca2+ channels (TTCCs) in the generation of new myocytes derived from either CSCs or proliferative cardiac myocytes after MI. Our recent work shows that CBSCs are a novel cell with the capacity to improve cardiac function in mouse MI models. The new work will define the mechanisms (differentiation into new cardiac tissue and/or enhancing endogenous repair of the native heart) of CBSC-mediated repair. A novel lineage tracing approach will be used to unambiguously examine these issues. These studies will also determine if enhancing Cn43 coupling of CBSCs and cardiac myocytes enhances stem cell survival and differentiation into new cardiac myocytes. Our recent work also shows that TTCCs regulate stem cell proliferation and commitment to the cardiac lineage.
In Aim 2 studies we will determine if modulation of TTCCs in cKit+ CSCs alters the ability of these cells to form new cardiac myocytes after MI. Finally we will perform proof of concept experiments without most efficacious cells (defined in mice) in a pig MI model, to document that the strategies being developed have the potential to translate to patients with ischemic heart disease.

Public Health Relevance

Myocardial infarction (MI) is a major health problem in the US. MI leads to poor performance of the heart because of the death of cardiac muscle cells. Our project will explore novel cells that appear to have an enhanced ability to repair the heart that has been injured by MI. The science proposed culminates in a proof of concept test of the most promising cell type in a large animal model. These studies could lead to early stage clinical trial and eventually in improved MI therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Application #
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Krull, Holly
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Temple University
Schools of Medicine
United States
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Borghetti, Giulia; von Lewinski, Dirk; Eaton, Deborah M et al. (2018) Diabetic Cardiomyopathy: Current and Future Therapies. Beyond Glycemic Control. Front Physiol 9:1514
Troupes, Constantine D; Wallner, Markus; Borghetti, Giulia et al. (2017) Role of STIM1 (Stromal Interaction Molecule 1) in Hypertrophy-Related Contractile Dysfunction. Circ Res 121:125-136
Wallner, Markus; Eaton, Deborah M; Berretta, Remus M et al. (2017) A Feline HFpEF Model with Pulmonary Hypertension and Compromised Pulmonary Function. Sci Rep 7:16587
Wang, Wei Eric; Li, Liangpeng; Xia, Xuewei et al. (2017) Dedifferentiation, Proliferation, and Redifferentiation of Adult Mammalian Cardiomyocytes After Ischemic Injury. Circulation 136:834-848
Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686
Sharp 3rd, Thomas E; Schena, Giana J; Hobby, Alexander R et al. (2017) Cortical Bone Stem Cell Therapy Preserves Cardiac Structure and Function After Myocardial Infarction. Circ Res 121:1263-1278
Cho, Gun-Sik; Lee, Dong I; Tampakakis, Emmanouil et al. (2017) Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy. Cell Rep 18:571-582
Harper, Shavonn C; Brack, Andrew; MacDonnell, Scott et al. (2016) Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects? Circ Res 118:1143-50; discussion 1150
Wallner, Markus; Duran, Jason M; Mohsin, Sadia et al. (2016) Acute Catecholamine Exposure Causes Reversible Myocyte Injury Without Cardiac Regeneration. Circ Res 119:865-79
Leipsic, Jonathon A (2015) President's Page. J Cardiovasc Comput Tomogr 9:604-5

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