Catalase therapy for cardiac regeneration

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DESCRIPTION (provided by applicant): The major cause of heart failure is regional loss of myocardium following myocardial infarction. Because the loss of tissue is highly localized, and the endogenous response is not sufficient, recent efforts have focused on replacement of the lost cells using a variety of treatment options. These include, but are not limited to, cell therapy, gene therapy and biomaterial-based grafts. Cell based therapies have been met with enthusiasm, however much debate still lingers on the optimal delivery method of cells and exact cell type which holds the most promise. Indeed, many cells most likely diffuse away from the site of injection, making biomaterial-based grafts more feasible. These grafts, while promising have many shortcomings when combined with cell therapy including poor cell engraftment, survival and differentiation. Oxidative stress is greatly increased in the myocardium following infarction. The increased superoxide following infarction not only increases damage to the local myocardium, but through dismutation to hydrogen peroxide may increase lipid peroxidation and cardiac fibrosis. Myocardial levels of the hydrogen peroxide scavenger catalase successively decrease in the weeks following infarction and its absence may also lead to incomplete regeneration by resident stem cells. Additionally, several therapies reported to improve cardiac function following infarction also increased catalase levels. Finally, oxidative stress may play a role in the survival and efficacy of cardiac stem cells during aging. Therefore, my research goals will center on the overall hypothesis that local hydrogen peroxide production following myocardial infarction plays an important role in the adaptive and maladaptive responses during cardiac regeneration. We will use transgenic mouse models, cell culture, and biomaterials to demonstrate a strong role for catalase in post-infarct remodeling. Better understanding of the role of catalase therapy, especially as it relates to cell type and timing could lead to improved therapeutic interventions for cardiac dysfunction. PUBLIC HEALTH RELEVANCE: Congestive heart failure is a leading cause of morbidity and mortality worldwide and effective treatment options are greatly needed. We propose to determine the role of hydrogen peroxide scavenging by catalase in the regenerative response. Studies to be performed include cardiac and inflammatory cell-specific overexpression, followed by myocardial infarction, as well as studies involving cell therapy with cardiac stem cells.