Functional relevance of cardiac regeneration by c-kit positive stem cells

摘要 心力衰竭是一个日益严重的医学和社会问题。目前的治疗方法不足以修复 心脏，只是延缓死亡。干细胞疗法有望成为一种有可能治愈 通过用新的健康的心肌细胞取代死亡的心肌和疤痕组织而导致的心力衰竭。直到十年前 以前，心脏被认为是有丝分裂后的器官。然而，新的发现表明，心脏 一些再生能力。潜在的相关更新来源包括骨髓来源的细胞，如 作为间充质干细胞、造血干细胞或内皮祖细胞，干细胞驻留在 心脏，即所谓的心脏祖细胞或心肌细胞的有丝分裂。所有这些来源都是 目前正在研究中，尽管关于心脏能够在多大程度上 再生。目前用于研究心脏再生依赖于心肌梗死的模型，通过 导致巨大的疤痕，缺乏血液供应。然后分离、培养和注射心脏干细胞 回到动物体内，研究它们的打捞能力。在这项提案中，我们将采取活体方法来 研究再生的内源性水平。我们将通过实现以下目标来研究再生： (1)用一种新的广泛随机方法检测内源性干细胞和CPC的激活 整个心脏的心肌细胞凋亡。(2)确定c-kit阳性(心脏)干细胞的重要性 利用基因工程小鼠的心脏再生细胞。(3)确定心脏有多重要 再生是为了心脏功能以及通过一个新的细胞更新程度的评估 小鼠基因模型追踪新生成的心肌细胞。研究提案的最初部分将是 由杰弗里·莫尔肯丁博士在实验室进行，他是一位研究心脏疾病的世界著名心脏研究员。 利用遗传小鼠模型研究肥大、钙信号和细胞死亡。在本实验中，我将生成不同的 研究体内心脏再生的小鼠模型，我将用它来完成这里提出的目标。 此外，这将为我提供机会开始我的独立研究生涯，专注于心脏 再生。这项提议将通过允许对以下因素的研究打开心脏再生的领域 可增强内源性心脏修复水平。最后，我们将开始确定 心脏再生对心脏功能的影响，并评估一种特定的干细胞群体在 心脏修复的过程。

Abstract Heart failure is a growing medical and social problem. Current medical therapies are insufficient to repair the heart and merely postpone death. Stem cell therapy holds promise to be a therapy that could potentially cure heart failure by replacing dead myocardium and scar tissue with new healthy cardiomyocytes. Until a decade ago the heart was considered to be a post-mitotic organ. New findings however, have suggested the heart has some regenerating capacity. Potentially relevant sources of renewal include bone marrow derived cells, such as mesenchymal stem cells, hematopoietic stem cells or endothelial progenitor cells, stem cells residing in the heart, so called Cardiac Progenitor Cells (CPCs) or mitosis by cardiomyocytes. All of these sources are currently being studied, although there is intense debate over the extent to which the heart is capable of regeneration. Currently used models to study cardiac regeneration rely on myocardial infarction, through the induction of a large scar that lacks blood supply. Cardiac stem cells are then isolated and cultured and injected back into the animal to study their salvaging capacities. In this proposal we will take an in vivo approach to study endogenous levels of regeneration. We will investigate regeneration by carrying out the following aims: (1) To examine endogenous stem cell and CPC activation using a novel method for widespread stochastic cardiomyocyte apoptosis throughout the heart. (2) To determine the importance of c-kit positive (cardiac) stem cells for cardiac regeneration using genetically engineered mice. (3) To determine how important cardiac regeneration is for cardiac function as well as assessment of the extent of cellular renewal through a new genetic mouse model to track newly generated myocytes. The initial part of the research proposal will be carried out in the lab or Dr. Jeffery Molkentin, a world renowned cardiac researcher who studies cardiac hypertrophy, calcium signaling and cell death using genetic mouse models. In this lab, I will generate different mouse models to study cardiac regeneration in vivo that I will use to complete the aims proposed here. Moreover, this will provide me with the opportunity to start my independent research career focused on cardiac regeneration. This proposal will open up the field of cardiac regeneration by allowing the study of factors that can enhance the endogenous levels of cardiac repair. Finally, we will begin to determine the relevance of cardiac regeneration for cardiac function and assess the importance of one specific population of stem cells in the process of cardiac repair.