Abstract

Chronic heart failure affects 4.8 million Americans, with 400,000 new cases every year. The leading cause of this condition includes acute myocardial infarction and repetitive myocardial ischemia. Although current methods of treatment are effective for restoring myocardial blood flow, they cannot prevent cardiac damage caused by ischemia and reperfusion, nor regenerate the lost myocardium. Therapeutic delivery of cardioprotective genes has proven effective in protecting the heart from ischemia/reperfusion injury. Very recently, adult stem cell therapy is emerging as a potential strategy for regenerating lost myocardium. However, the efficacy of this approach is limited by the small number of stem cells that can populate, survive and differentiate in ischemic heart tissues. We hypothesize that these problems can be solved by a hypoxia regulated therapeutic gene transfer using safe and low-risk delivery vectors. Therefore, the objective of this proposal is to develop a combined strategy of regulated gene transfer and stem cell therapy to provide comprehensive protection and regeneration to ischemic hearts.
The specific aims are: 1. To protect the heart from ischemic injury by hypoxia-regulated heme oxygenase-1 (HO-1) expression. We will express a cytoprotective enzyme HO-1 in ischemic hearts by recombinant adeno-associated viral(rAAV) vectors and test the protective effects in a murine model of myocardial infarction. 2. To target bone marrow-derived stem cells to ischemic hearts by hypoxia-regulated stromal cell-derived factor-1 (SDF-1) expression. We will deliver a stem cell homing factor SDF-1 specifically to ischemic hearts via rAAV-mediated gene transfer to attract circulating stem cells. 3 .To enhance stem cell survival in ischemic hearts by genetic engineering of stem cells to express hypoxia-regulated HO-I. We will engineer bone marrow-derived stem cells to express HO-1 via ex vivo rAAV infection and evaluate their capacity to survive in ischemic myocardium and to improve cardiac function.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077602-04
Application #
7274209
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2004-07-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$359,123
Indirect Cost

  Institution

Name
Keck Graduate Institute of Applied Life Scis
Department
Type
DUNS #
011116907
City
Claremont
State
CA
Country
United States
Zip Code
91711

  Publications

Fernandes, Tiago; Baraúna, Valério G; Negrão, Carlos E et al. (2015) Aerobic exercise training promotes physiological cardiac remodeling involving a set of microRNAs. Am J Physiol Heart Circ Physiol 309:H543-52
Fernandes, Tiago; Magalhães, Flávio C; Roque, Fernanda R et al. (2012) Exercise training prevents the microvascular rarefaction in hypertension balancing angiogenic and apoptotic factors: role of microRNAs-16, -21, and -126. Hypertension 59:513-20
DA Silva Jr, Natan D; Fernandes, Tiago; Soci, Ursula P R et al. (2012) Swimming training in rats increases cardiac MicroRNA-126 expression and angiogenesis. Med Sci Sports Exerc 44:1453-62
Fernandes, Tiago; Hashimoto, Nara Y; Magalhães, Flávio C et al. (2011) Aerobic exercise training-induced left ventricular hypertrophy involves regulatory MicroRNAs, decreased angiotensin-converting enzyme-angiotensin ii, and synergistic regulation of angiotensin-converting enzyme 2-angiotensin (1-7). Hypertension 58:182-9
Soci, U P R; Fernandes, T; Hashimoto, N Y et al. (2011) MicroRNAs 29 are involved in the improvement of ventricular compliance promoted by aerobic exercise training in rats. Physiol Genomics 43:665-73
Tang, Yao Liang; Zhu, Wuqiang; Cheng, Min et al. (2009) Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression. Circ Res 104:1209-16
Phillips, M Ian; Tang, Yao Liang (2008) Genetic modification of stem cells for transplantation. Adv Drug Deliv Rev 60:160-72
Phillips, M Ian; de Oliveira, Edilamar Menezes (2008) Brain renin angiotensin in disease. J Mol Med 86:715-22
Tang, Yao Liang; Shen, Leping; Qian, Keping et al. (2007) A novel two-step procedure to expand cardiac Sca-1+ cells clonally. Biochem Biophys Res Commun 359:877-83
Tang, Yao Liang; Phillips, Michael Ian (2007) Invited commentary. Ann Thorac Surg 83:1499-500

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