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

描述（由申请人提供）：心力衰竭是一个日益严重的医学和社会问题。目前的医学疗法不足以修复心脏，只能推迟死亡。干细胞疗法有望成为一种通过用新的健康心肌细胞替代死亡心肌和瘢痕组织来治愈心力衰竭的疗法。直到十年前，心脏还被认为是一个有丝分裂后的器官。然而，新的发现表明心脏具有一定的再生能力。潜在相关的更新来源包括骨髓来源的细胞，例如间充质干细胞、造血干细胞或内皮祖细胞、驻留在心脏中的干细胞，所谓的心脏祖细胞（CPC）或心肌细胞的有丝分裂。所有这些来源目前都在研究中，尽管关于心脏再生能力的程度存在激烈的争论。目前用于研究心脏再生的模型依赖于心肌梗死，通过诱导缺乏血液供应的大疤痕。然后分离和培养心脏干细胞，并将其注射回动物体内以研究其挽救能力。在本提案中，我们 将采用体内方法来研究内源性再生水平。我们将通过以下目的来研究再生：（1）使用一种新的方法来检测内源性干细胞和CPC的激活，用于在整个心脏中广泛随机的心肌细胞凋亡。(2)利用基因工程小鼠确定c-kit阳性（心脏）干细胞对心脏再生的重要性。(3)确定心脏再生对心脏功能的重要性，以及通过一种新的遗传小鼠模型跟踪新生成的心肌细胞来评估细胞更新的程度。研究提案的最初部分将在实验室或Jeffery Molkentin博士进行，Jeffery Molkentin博士是世界著名的心脏研究人员，他使用遗传小鼠模型研究心脏肥大，钙信号传导和细胞死亡。在这个实验中，我将生成不同的小鼠模型来研究体内心脏再生，我将使用这些模型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。该提案将通过允许研究可以增强心脏修复的内源性水平的因素来打开心脏再生的领域。最后，我们将开始确定心脏再生与心脏功能的相关性，并评估一个特定的干细胞群体在心脏修复过程中的重要性。

DESCRIPTION (provided by applicant): 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.