Diabetes leads to myocardial dysfunction in the absence of coronary artery disease (CAD). This condition, diabetic cardiomyopathy (DCM), has been postulated to contribute to higher incidences of both congestive HF and mortality in diabetic patients. Even more serious is the occurrence, of HF following myocardial infarction (Ml) in long-standing diabetics, as diabetes induces adverse cardiac remodeling after Ml and leads to more severe HF. HF in diabetes with or without CAD (collectively referred to as diabetic HF) poses a major threat to public health as the incidence of diabetes rises, and as medical management prolongs the life span of diabetics. Despite these unique features of diabetic HF and the foreseen public health disaster due to the poor prognosis of diabetic HF, there have been no specific therapies targeting the principal pathophysiologic problems of diabetic heart diseases. We recently identified that impaired angiogenesis (formation of new vasculature from pre-existing mature endothelial cells) and decreased availability of circulating endothelial progenitor cells (EPCs) play a major role in the development of DCM. Recent identification of EPCs derived from adult bone marrow, which contribute to de novo development of vessels (vasculogenesis), has raised the possibility of utilizing these cells to repair ischemic/infarcted myocardium by inducing new vessel formation through the processes of vasculogenesis and angiogenesis. The long-term goal of this project is to define the role of the vasculature and its related biological factors in the development of diabetic HF and to establish more effective therapeutic strategies to treat diabetic HF. Accordingly, in this Proposal, we designed a series of experiments to investigate the role of angiogenesis and vasculogenesis in the development of diabetic HF and the impact of EPC transplantation on diabetic HF.
In Specific Aim 1, we will investigate the role of defective myocardial angiogenesis and EPCs in the development of diabetic HF.
In Specific Aim 2, we will explore the therapeutic impact of EPC transplantation on diabetic HF by using DCM and diabetic Ml models.
In Specific Aim 3, we will investigate potential mechanisms which mediate the therapeutic effect of EPC transplantation. For this series of experiments, we will use streptozotocin-induced diabetic rat and mouse models and perform comprehensive functional, molecular and histopathologic examinations on the hearts and EPCs. We anticipate that the results of the experiments outlined in this proposal will yield new insight into the pathophysiologic features of diabetic HF and the application of innovative stem/progenitor cell therapy for repairing or preventing myocardial injury associated with diabetes. The successful completion of these studies should provide novel therapeutic strategies to address a clinical disorder that accounts for major morbidity and mortality and has to date been inadequately addressed by available clinical therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL084471-06
Application #
7809469
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Przywara, Dennis
Project Start
2006-04-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
6
Fiscal Year
2010
Total Cost
$376,263
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Jeong, Jin-Ok; Han, Ji Woong; Kim, Jin-Man et al. (2011) Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. Circ Res 108:1340-7
Kim, Sung-Whan; Kim, Hyongbum; Yoon, Young-sup (2011) Advances in bone marrow-derived cell therapy: CD31-expressing cells as next generation cardiovascular cell therapy. Regen Med 6:335-49
Han, Ji Woong; Yoon, Young-Sup (2011) Induced pluripotent stem cells: emerging techniques for nuclear reprogramming. Antioxid Redox Signal 15:1799-820
Kim, Sung-Whan; Yoon, Young-Sup (2010) True autologous approach in cell therapy. - Using your own serum for cell culture -. Circ J 74:852-3
Kim, Sung-Whan; Kim, Hyongbum; Cho, Hyun-Jai et al. (2010) Human peripheral blood-derived CD31+ cells have robust angiogenic and vasculogenic properties and are effective for treating ischemic vascular disease. J Am Coll Cardiol 56:593-607
Kim, Hyongbum; Cho, Hyun-Jai; Kim, Sung-Whan et al. (2010) CD31+ cells represent highly angiogenic and vasculogenic cells in bone marrow: novel role of nonendothelial CD31+ cells in neovascularization and their therapeutic effects on ischemic vascular disease. Circ Res 107:602-14
Lee, Ji Yoon; Park, Changwon; Cho, Yong Pil et al. (2010) Podoplanin-expressing cells derived from bone marrow play a crucial role in postnatal lymphatic neovascularization. Circulation 122:1413-25
Kim, Hyongbum; Kim, Sung-Whan; Nam, Douglas et al. (2009) Cell therapy with bone marrow cells for myocardial regeneration. Antioxid Redox Signal 11:1897-911
Kim, Hyongbum; Park, Jong-seon; Choi, Yong Jin et al. (2009) Bone marrow mononuclear cells have neurovascular tropism and improve diabetic neuropathy. Stem Cells 27:1686-96
Jeong, Jin-Ok; Kim, Mee-Ohk; Kim, Hyongbum et al. (2009) Dual angiogenic and neurotrophic effects of bone marrow-derived endothelial progenitor cells on diabetic neuropathy. Circulation 119:699-708

Showing the most recent 10 out of 12 publications