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

c-kit 阳性干细胞与心脏再生的功能相关性

基本信息

批准号：
8854129
负责人：
Johannes (Jop) Van Berlo
金额：
$ 23.67万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-04 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8854129
关键词：
Adult Animals Apoptosis Back Bone Marrow Bone Marrow Stem Cell Calcium Signaling Cardiac Cardiac Myocytes Cardiac development Cell Cycle Cell Death Cell Proliferation Cells Cessation of life Characteristics Cicatrix Development Engraftment Environment Exercise Flow Cytometry Funding Opportunities Future Genetic Genetic Transcription Genetically Engineered Mouse Heart Heart Hypertrophy Heart failure Hematopoietic stem cells Histology Home environment Knock-in Mouse Label Mediating Medical Mesenchymal Stem Cells Methods Mitosis Mitotic Modeling Morphologic artifacts Muscle Cells Myocardial Infarction Myocardium Natural regeneration Organ Physiological Play Population Process Proto-Oncogene Protein c-kit Relative (related person)Reporter Research Research Personnel Research Proposals Role Social Problems Source Stem cells System Tamoxifen Techniques Tissues Toxin Transgenes Vascular blood supply abstracting base cardiac regeneration cardiac repair career fetal in vivo injured killings mouse model novel pressure progenitor recombinase regenerative repaired stem cell population stem cell therapy

项目摘要

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.

抽象的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，只是推迟死亡。干细胞疗法有望成为一种可能治愈的疗法用新的健康心肌细胞替换死亡的心肌和疤痕组织，从而导致心力衰竭。直到十年以前，心脏被认为是有丝分裂后的器官。然而，新的发现表明心脏已经一定的再生能力。潜在的相关更新来源包括骨髓衍生细胞，例如作为间充质干细胞、造血干细胞或内皮祖细胞，干细胞存在于心脏，所谓的心脏祖细胞（CPC）或心肌细胞的有丝分裂。所有这些来源都是目前正在研究中，尽管对于心脏的能力程度存在激烈的争论再生。目前用于研究心脏再生的模型依赖于心肌梗塞，通过诱导缺乏血液供应的大疤痕。然后分离培养心脏干细胞并注射回到动物体内，研究它们的救援能力。在本提案中，我们将采用体内方法研究再生的内源水平。我们将通过实现以下目标来研究再生： (1) 使用广泛随机的新方法检查内源干细胞和 CPC 激活整个心脏的心肌细胞凋亡。 (2) 确定c-kit阳性（心脏）干细胞的重要性使用基因工程小鼠进行心脏再生的细胞。 (3)确定心脏的重要性再生用于心脏功能以及通过新的方法评估细胞更新的程度追踪新生成的肌细胞的遗传小鼠模型。研究计划的初始部分将是在杰弗里·莫尔肯廷 (Jeffery Molkentin) 博士的实验室中进行，他是世界著名的心脏研究人员，研究心脏使用遗传小鼠模型研究肥大、钙信号传导和细胞死亡。在这个实验室中，我将生成不同的用于研究体内心脏再生的小鼠模型，我将使用它来完成此处提出的目标。此外，这将为我提供开始我的独立研究生涯的机会，专注于心脏再生。该提案将通过研究影响心脏再生的因素，开辟心脏再生领域。可以增强心脏修复的内源性水平。最后，我们将开始确定相关性心脏再生对心脏功能的影响，并评估一种特定干细胞群在心脏中的重要性心脏修复的过程。