Myocardium and Conduction System from ESCs

ESC 的心肌和传导系统

• 批准号: 6909658
• 负责人: MICHAEL Alan LAFLAMME
• 金额: $ 12.56万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909658
• 关键词: biomarker; cardiac myocytes; cell differentiation; cell sorting; cell transplantation; embryonic stem cell; fluorescent dye /probe; heart conduction system; heart contraction; histology; human embryonic stem cell line; human genetic material tag; laboratory rat; myocardial infarction; regeneration; therapy design /development

DESCRIPTION (provided by applicant): The primary goal of this proposal is to train the principal investigator to become an independent physician-scientist in the field of cardiac stem cell and regenerative biology. He proposes a detailed program of career development and a research plan involving human embryonic stem cell (hESC) derived cardiomyocytes. The training plan includes coursework, conferences, specialized instruction, and formation of an advisory committee to foster career development as a physician-scientist. In preliminary experiments, we demonstrated that grafting of hESC-derived cardiomyocytes into both uninjured and infracted hearts of immunodeficient rats produced human myocardium in vivo. Parallel in vitro work has identified highly promising strategies for deriving enriched cultures of human embryonic cardiomyocytes. The candidate exploits opportunities presented by this work in proposing the following specific aims: 1) optimize implants of hESC-derived myocardium in the infracted rat heart and determine whether this results in improved mechanical function; 2) to test the hypothesis that hESC-derived cardiomyocyte grafts will show electromechanical coupling with the adjacent host myocardium; 3) to test the hypothesis that with in vivo maturation, grafted hESC-derived myocardium will show phenotypic alterations in excitation-contraction coupling; and 4) develop strategies for the purification and/or induced differentiation of specialized cardiac conduction system cells from hESC-derived cardiomyocytes. The University of Washington represents an outstanding environment both for such studies and for the development of physician-scientists, a situation will be further enhanced through an institutional commitment to establish a Center for Cardiovascular & Regenerative Medicine. Combined with the support of the present career award, this environment will allow the principal investigator to acquire the technical and critical thinking skills to commence a successful independent line of investigation.

描述（由申请人提供）： 该提案的主要目标是培训主要研究者成为心脏干细胞和再生生物学领域的独立医师科学家。 他提出了详细的职业发展计划和涉及人类胚胎干细胞（hESC）衍生心肌细胞的研究计划。 培训计划包括课程作业、会议、专业指导以及组建咨询委员会以促进医师科学家的职业发展。 在初步实验中，我们证明将 hESC 衍生的心肌细胞移植到免疫缺陷大鼠未受伤和梗塞的心脏中，可在体内产生人心肌。 平行的体外工作已经确定了用于获得人类胚胎心肌细胞富集培养物的非常有前途的策略。 候选人利用这项工作提供的机会提出以下具体目标：1）优化梗死大鼠心脏中 hESC 衍生心肌的植入，并确定这是否会改善机械功能； 2) 检验 hESC 衍生的心肌细胞移植物将与邻近宿主心肌表现出机电耦合的假设； 3) 检验以下假设：随着体内成熟，移植的 hESC 来源的心肌将表现出兴奋-收缩耦合的表型改变； 4) 制定从 hESC 衍生的心肌细胞中纯化和/或诱导分化专门的心脏传导系统细胞的策略。 华盛顿大学为此类研究和医师科学家的发展提供了良好的环境，通过建立心血管和再生医学中心的机构承诺将进一步改善这种情况。 结合当前职业奖的支持，这种环境将使主要调查员能够获得技术和批判性思维技能，以开始成功的独立调查。