Catalase therapy for cardiac regeneration

描述(申请人提供)：心力衰竭的主要原因是心肌梗死后局部心肌丢失。由于组织的丢失是高度局部性的，内源性反应还不够充分，最近的努力集中在使用各种治疗方案来替换丢失的细胞。这些包括但不限于细胞疗法、基因疗法和基于生物材料的移植。基于细胞的治疗受到了热烈的欢迎，但关于细胞的最佳输送方法和确切的细胞类型仍然存在许多争论，其中最有希望的是什么。事实上，许多细胞很可能从注射部位扩散开来，使基于生物材料的移植更加可行。这些移植物虽然前景看好，但与细胞治疗相结合时，存在许多缺点，包括细胞植入、存活和分化能力差。心肌梗死后氧化应激显著增加。心肌梗死后超氧化物歧化不仅增加局部心肌的损伤，而且通过歧化为过氧化氢可能增加脂质过氧化和心肌纤维化。心肌中过氧化氢清除剂过氧化氢酶的水平在梗塞后的几周内连续下降，缺乏过氧化氢也可能导致常驻干细胞的不完全再生。此外，据报道，几种改善脑梗塞后心功能的疗法也提高了过氧化氢酶水平。最后，氧化应激可能在衰老期间心脏干细胞的存活和疗效中发挥作用。因此，我的研究目标将集中在一个总体假设上，即心肌梗死后局部过氧化氢的产生在心脏再生过程中的适应性和非适应性反应中发挥重要作用。我们将使用转基因小鼠模型、细胞培养和生物材料来证明过氧化氢酶在脑梗塞后重塑中的重要作用。更好地理解过氧化氢酶疗法的作用，特别是当它与细胞类型和时机有关时，可能会导致改善心功能障碍的治疗干预。 公共卫生相关性：充血性心力衰竭是世界范围内发病率和死亡率的主要原因，非常需要有效的治疗方案。我们建议确定过氧化氢酶清除过氧化氢在再生反应中的作用。将要进行的研究包括心脏和炎症细胞特异性的过度表达，随后是心肌梗死，以及涉及心脏干细胞细胞治疗的研究。

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.