Catalase therapy for cardiac regeneration

描述（由申请人提供）：心力衰竭的主要原因是心肌梗死后的局部心肌丢失。因为组织的损失是高度局部化的，并且内源性反应是不充分的，所以最近的努力集中在使用各种治疗选择来替换损失的细胞。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物。基于细胞的疗法已经受到了热情的欢迎，然而，关于细胞的最佳递送方法和最有希望的确切细胞类型的争论仍然存在。事实上，许多细胞很可能从注射部位扩散出去，使得基于生物材料的移植物更加可行。这些移植物虽然有希望，但在与细胞疗法组合时具有许多缺点，包括差的细胞移植、存活和分化。 心肌梗死后氧化应激大大增加。心肌梗死后超氧化物的增加不仅增加了局部心肌的损伤，而且通过歧化为过氧化氢可增加脂质过氧化和心肌纤维化。心肌过氧化氢清除剂过氧化氢酶的水平在梗死后的几周内连续下降，其缺乏也可能导致常驻干细胞的不完全再生。此外，几种治疗报告，以改善心肌梗死后的心脏功能也增加过氧化氢酶水平。最后，氧化应激可能在衰老过程中心脏干细胞的存活和功效中发挥作用。因此，我的研究目标将集中在总体假设，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适应不良反应中起着重要作用。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梗死后重塑中的重要作用。 更好地理解过氧化氢酶治疗的作用，特别是当它与细胞类型和时机有关时，可能会改善心功能不全的治疗干预。 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，以确定过氧化氢清除再生反应中的作用过氧化氢酶。将要进行的研究包括心脏和炎症细胞特异性过表达，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.