Catalase therapy for cardiac regeneration

过氧化氢酶治疗心脏再生

• 批准号: 8449194
• 负责人: Michael E Davis
• 金额: $ 35.04万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449194
• 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.

描述（由申请人提供）：心力衰竭的主要原因是心肌梗塞后心肌的局部损失。由于组织损失是高度局部性的，并且内源性反应不充分，因此最近的努力集中在使用各种治疗方案来替代损失的细胞。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很多争论。事实上，许多细胞很可能从注射部位扩散开，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，但与细胞疗法结合时存在许多缺点，包括细胞植入、存活和分化较差。 梗塞后心肌中的氧化应激大大增加。梗塞后超氧化物的增加不仅增加了对局部心肌的损伤，而且通过歧化为过氧化氢可能会增加脂质过氧化和心脏纤维化。心肌梗塞后数周内过氧化氢清除剂过氧化氢酶的水平逐渐降低，其缺失也可能导致驻留干细胞再生不完全。此外，据报道，几种可以改善梗塞后心脏功能的疗法也可以提高过氧化氢酶水平。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这样一个总体假设上：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发挥重要作用。我们将使用转基因小鼠模型、细胞培养物和生物材料来证明过氧化氢酶在梗塞后重塑中的强大作用。 更好地了解过氧化氢酶疗法的作用，特别是它与细胞类型和时间的关系，可能会改善心脏功能障碍的治疗干预措施。

项目成果

Dysregulation of catalase activity in newborn myocytes during hypoxia is mediated by c-Abl tyrosine kinase.

缺氧期间新生肌细胞中过氧化氢酶活性的失调是由 c-Abl 酪氨酸激酶介导的。

• 发表时间: 2015-01
• 影响因子: 2.6
• 作者: Cabigas, E Bernadette;Liu, Jie;Boopathy, Archana V;Che, Pao Lin;Crawford, Brian H;Baroi, Gitangali;Bhutani, Srishti;Shen, Ming;Wagner, Mary B;Davis, Michael E
• 通讯作者: Davis, Michael E

Oxidative stress-induced Notch1 signaling promotes cardiogenic gene expression in mesenchymal stem cells.

氧化应激诱导的 Notch1 信号传导促进间充质干细胞中的心肌基因表达。

• 发表时间: 2013-04-18
• 影响因子: 7.5
• 作者: Boopathy, Archana V;Pendergrass, Karl D;Che, Pao Lin;Yoon, Young;Davis, Michael E
• 通讯作者: Davis, Michael E

Isolation and expansion of c-kit-positive cardiac progenitor cells by magnetic cell sorting.

通过磁性细胞分选分离和扩增 c-kit 阳性心脏祖细胞。

• DOI: 10.1007/978-1-4939-1047-2_4
• 发表时间: 2024-09-14
• 期刊: Methods in molecular biology
• 作者: Kristin M. French;Michael E. Davis
• 通讯作者: Michael E. Davis

Self-assembling peptide-based delivery of therapeutics for myocardial infarction.

基于自组装肽的心肌梗塞治疗药物递送。

• DOI: 10.1007/978-1-4939-0363-4_10
• 发表时间: 2024-09-14
• 期刊: Methods in molecular biology
• 作者: A. V. Boopathy;Michael E. Davis
• 通讯作者: Michael E. Davis