Human Pluripotent Stem Cell and Progenitor Models of Cardiac and Blood Diseases

人类多能干细胞和心脏和血液疾病的祖细胞模型

基本信息

批准号：
7833974
负责人：
KENNETH R CHIEN
金额：
$ 131.55万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7833974
关键词：
Americas Becker Muscular Dystrophy Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cardiovascular system Cell Differentiation process Cell Line Cell Proliferation Cell model Cells Characteristics Clinical Development Disease Drug Design Dystrophin ES Cell Line Elastomers Engineering Film Foundations Genetic Heart failure Hematological Disease Human In Vitro Laboratories Link Medicine Modeling Modeling of Cellular Pathways Mus Muscle Cells Mutation Myocardial Myocardial tissue Pathway interactions Patients Pharmacotherapy Phenotype Pluripotent Stem Cells Principal Investigator Protocols documentation Reagent Regenerative Medicine Role Signal Pathway Signal Transduction Source Stem cells Technology Testing Therapeutic Tissue Engineering Tissues Transgenic Organisms Ventricular base drug development induced pluripotent stem cell mortality novel progenitor regenerative regenerative therapy stem cell biology two-dimensional

项目摘要

DESCRIPTION (provided by applicant): Advanced heart failure represents a major unmet clinical need, arising from the loss of viable or fully functional cardiac muscle cells. Despite optimum drug therapy, heart failure is a leading cause of mortality in America. Generating functional myocardial tissue from a renewable patient-specific source would allow for the development of disease specific cellular models for pathway identification and drug development. It would also lay the foundation for therapeutic cardiac regenerative medicine. We propose to integrate the unique expertise, reagents, and protocols from four leading laboratories in cardiac stem cell biology and development (Chien/Wu), human ES and IPS technology (Melton), and cardiac tissue engineering (Parker), to generate patient-specific myocardial tissue as cellular models for human cardiovascular disease, and as a foundation for cell-based regenerative therapy. Accordingly, the specific aims of our proposed project are the following. AIM 1: Identify non-cell autonomous signaling pathways that control cardiovascular progenitor cell (CVP) expansion and differentiation. We hypothesize that specific non-cell autonomous signaling pathways control murine CVP expansion and differentiation. AIM 2: Determine if murine iPS-derived CVPs recapitulate normal cardiac development and can be used to generate functional myocardial tissue in vitro. We hypothesize that IPS derived cardiac progenitors are similar to ESC-derived cardiac progenitors in developmental potential and functional characteristics. AIM 3: Isolate and characterize CVPs from human ES and IPS cells. We hypothesize that during human ES and iPS cell differentiation, cardiac myocytes are generated by the commitment of cardiac progenitors into CVPs which then differentiate into fully mature ventricular myocytes. AIM 4: Generate cellular models for human cardiovascular disease such as X-linked cardiomyopathy (i.e. cardiomyopathies caused by dystrophin mutations such as those in Duchenne's and Becker's muscular dystrophy). We hypothesize that disease specific CVP will recapitulate diseased myocardial phenotype, as well as diseased myocardial phenotype. This will serve as a platform for genetic pathway discovery, drug design, and regenerative cardiovascular medicine.

描述（由申请人提供）：晚期心力衰竭代表了由于丧失或功能齐全的心肌细胞的丧失而产生的主要未满足临床需求。尽管药物治疗最佳，但心力衰竭是美国死亡率的主要原因。从可再生患者特异性来源产生功能性心肌组织将允许开发特定于疾病的细胞模型，以识别途径和药物发育。它还将为治疗性心脏再生医学奠定基础。我们建议将四个主要实验室的独特专业知识，试剂和协议整合到心脏干细胞生物学和发育（Chien/Wu），人ES和IPS技术（Melton）以及心脏组织工程（Parker），以生成患者特异性心肌疾病的细胞模型，用于人类心血管疾病的细胞模型。因此，我们提议的项目的具体目标是以下内容。目标1：确定控制心血管祖细胞（CVP）扩展和分化的非电池自主信号通路。我们假设特定的非细胞自主信号通路控制鼠CVP的扩展和分化。 AIM 2：确定鼠IPS衍生的CVP是否概括了正常的心脏发育，可用于在体外产生功能性心肌组织。我们假设IPS衍生的心脏祖细胞与发育潜力和功能特征的ESC衍生心脏祖细胞相似。 AIM 3：分离并表征来自人类ES和IPS细胞的CVP。我们假设在人ES和IPS细胞分化过程中，心肌细胞是通过心脏祖细胞对CVP的承诺而产生的，然后将其分化为完全成熟的心室心肌细胞。 AIM 4：为人类心血管疾病（例如X连锁心肌病）产生细胞模型（即由肌营养不良蛋白突变引起的心肌病，例如Duchenne's和Becker的肌肉营养不良）。我们假设特定于疾病的CVP将概括患病的心肌表型以及患病的心肌表型。这将成为遗传途径发现，药物设计和再生心血管医学的平台。