Catalase therapy for cardiac regeneration

过氧化氢酶治疗心脏再生

• 批准号: 8235809
• 负责人: Michael E Davis
• 金额: $ 36.66万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235809
• 关键词: Acute; Adhesions; Aftercare; Aging; Apoptosis; Biocompatible Materials; Cardiac; Cardiac Myocytes; Cell Culture Techniques; Cell Survival; Cell Therapy; Cells; Chronic; Congestive Heart Failure; Data; Diabetes Mellitus; Differentiation and Growth; Diffuse; Disease; Engineering; Engraftment; Fibroblasts; Fibrosis; Free Radicals; Functional disorder; Gene Proteins; Genetic; Goals; Growth Factor; Heart failure; Homing; Hydrogen Peroxide; Implant; In Vitro; Infarction; Inflammatory; Injection of therapeutic agent; Injury; Invaded; Lead; Lipid Peroxidation; Magnetic Resonance Imaging; Measures; Methods; Modeling; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Oxidative Stress; Peptides; Phase; Physiological; Plague; Play; Process; Production; Proteins; Publishing; Reporting; Research; Role; Site; Source; Staging; Staining method; Stains; Stem cells; Superoxides; System; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Transfection; Transgenic Mice; base; catalase; cell type; clinical application; design; effective therapy; extracellular; gene therapy; improved; in vivo; meetings; mortality; mouse model; nanofiber; neutrophil; overexpression; public health relevance; regenerative; repaired; response; scaffold

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.

描述（由申请人提供）：心衰的主要原因是心肌梗死后局部心肌丧失。由于组织的损失是高度局部的，并且内源性反应不充分，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治疗、基因治疗和基于生物材料的移植。基于细胞的疗法受到了热烈的欢迎，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仍然存在许多争论。事实上，许多细胞很可能会从注射部位扩散出去，这使得基于生物材料的移植更加可行。这些移植物虽然很有前景，但在与细胞治疗联合使用时存在许多缺点，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。梗死后超氧化物的增加不仅增加了局部心肌的损伤，而且通过过氧化氢的突变可能增加脂质过氧化和心脏纤维化。心肌过氧化氢清除剂过氧化氢酶水平在梗死后数周内持续下降，其缺失也可能导致驻留干细胞再生不完全。此外，据报道，一些改善梗死后心功能的疗法也增加了过氧化氢酶水平。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心肌梗死后局部过氧化氢产生在心脏再生过程中的适应和不适应反应中起重要作用的总体假设上。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构中的重要作用。更好地了解过氧化氢酶治疗的作用，特别是它与细胞类型和时间的关系，可能会改善心功能障碍的治疗干预。