Lack of understanding of basic stem cell mechanisms limits current therapeutic approaches. In this renewal application, we will focus on the use of c-kit* cardiac progenitor cells (CPCs) to protect the heart against post-myocardial infarction (Ml) remodeling and heart failure (HF). The overall goal is to elucidate the molecular mechanisms that regulate the properties of CPCs and to evaluate the therapeutic utility of enhancing CPC function in order to optimize cardiac repair. Four closely inter-related and inter-dependent Projects will address different facets of this theme. Project 1 (Belli) will elucidate the role of CO and NO in regulating CPC function and therapeutic efficacy. The central hypothesis is that these gases are kev determinants of CPC competence and that augmenting their levels will dramatically enhance CPC-mediated cardiac repair. Project 2 (Prabhu) will illuminate the deleterious effects of TNF on CPC competence and reparative ability. This project will test the hypothesis that differential TNF signaling via TNFR1, TNFR2, and NF-KB plavs a critical role in determining adrenergic versus cardiomyogenic fate and, consequently, the reparative capacity of CPCs following Ml. Project 3 (Jones) will examine the role of protein 0-GlcNAcylation in modulating the fundamental properties of CPCs and will test the hypothesis that the 0-GlcNAc alarm signal plays a critical role in regulating CPC proliferation, survival, differentiation, and paracrine function. Project 4 (Bhatnagar) will determine how diabetes affects CPC-mediated myocardial repair and how CPC therapy can be optimized for the diabetic heart. The central hypothesis is that diabetes undermines CPC competence by inducing insulin resistance. Thus, all four Projects focus cohesively on CPCs. These Projects will be supported by four Cores that will provide expertise in mouse surgery, cell transplantation, CPC culture and phenotyping, pathology, flow cytometry, and cell sorting. This highly-focused PPG will be led by investigators who have collaborated productively for many years. Their long history of collaboration has resulted in closely integrated Projects that are ideally suited for a PPG. These will be the first studies to examine the role of CO and NO, TNF, 0-GlcNAcylation, and type 2 diabetes on CPC function: consequently, the results will be entirely new and will advance our understanding of CPC biology. In addition, these studies may lay the groundwork for new translational investigations of CPC therapy in patients with HF. Since we have already initiated the first-in-humans clinical trial of unmodified CPCs in patients with HF, we are well positioned to rapidly translate any insights derived from this Program into new clinical investigations.

Public Health Relevance

In 2009, we started SCIPIO, the first-in-humans study of c-kit+ cardiac progenitor cells (CPCs). The initial results are encouraging. This Program builds on SCIPIO and seeks to optimize the effectiveness of these promising CPCs therapies. If our hypotheses are confirmed, the results will lead to the use of more efficacious cell therapies in patients with heart failure. Since we have developed the infrastructure to launch new clinical studies of CPCs, any new insights gained in this Program will be rapidly translated.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL078825-08
Application #
8492140
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Wong, Renee P
Project Start
2004-12-01
Project End
2016-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$2,437,090
Indirect Cost
$688,177
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Uchida, Shizuka; Jones, Steven P (2018) RNA Editing: Unexplored Opportunities in the Cardiovascular System. Circ Res 122:399-401
Wysoczynski, Marcin; Khan, Abdur; Bolli, Roberto (2018) New Paradigms in Cell Therapy: Repeated Dosing, Intravenous Delivery, Immunomodulatory Actions, and New Cell Types. Circ Res 123:138-158
Bolli, Roberto; Hare, Joshua (2018) Introduction to a Compendium on Regenerative Cardiology. Circ Res 123:129-131
Gibb, Andrew A; Hill, Bradford G (2018) Metabolic Coordination of Physiological and Pathological Cardiac Remodeling. Circ Res 123:107-128
Hindi, Sajedah M; Sato, Shuichi; Xiong, Guangyan et al. (2018) TAK1 regulates skeletal muscle mass and mitochondrial function. JCI Insight 3:
Mehra, Parul; Guo, Yiru; Nong, Yibing et al. (2018) Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair. Basic Res Cardiol 113:46
Baba, Shahid P; Zhang, Deqing; Singh, Mahavir et al. (2018) Deficiency of aldose reductase exacerbates early pressure overload-induced cardiac dysfunction and autophagy in mice. J Mol Cell Cardiol 118:183-192
Fulghum, Kyle; Hill, Bradford G (2018) Metabolic Mechanisms of Exercise-Induced Cardiac Remodeling. Front Cardiovasc Med 5:127
Hosen, Mohammed Rabiul; Militello, Giuseppe; Weirick, Tyler et al. (2018) Airn Regulates Igf2bp2 Translation in Cardiomyocytes. Circ Res 122:1347-1353
Dassanayaka, Sujith; Zheng, Yuting; Gibb, Andrew A et al. (2018) Cardiac-specific overexpression of aldehyde dehydrogenase 2 exacerbates cardiac remodeling in response to pressure overload. Redox Biol 17:440-449

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