Myocardium and Conduction System from ESCs

描述(由申请人提供)： 这项提议的主要目标是培训首席研究员，使其成为心脏干细胞和再生生物学领域的独立内科科学家。他提出了一个详细的职业发展计划和一个涉及人类胚胎干细胞(HESC)来源的心肌细胞的研究计划。培训计划包括课程作业、会议、专业指导和成立一个咨询委员会，以促进医生-科学家的职业发展。 在初步实验中，我们证明了将hESC来源的心肌细胞移植到免疫缺陷大鼠的未损伤和受损心脏中，在体内产生了人心肌。平行的体外工作已经确定了非常有希望的方法来获得丰富的人类胚胎心肌细胞培养。候选人利用这项工作带来的机会提出下列具体目标：1)优化hESC来源的心肌在梗死大鼠心脏的植入，并确定这是否会改善机械功能；2)测试hESC来源的心肌细胞移植将与邻近宿主心肌显示机电耦合的假设；3)测试随着体内成熟，移植的hESC来源的心肌将显示兴奋-收缩偶联的表型变化的假设；以及4)开发从hESC来源的心肌细胞纯化和/或诱导分化专门的心脏传导系统细胞的策略。 华盛顿大学为这类研究和内科科学家的发展提供了一个出色的环境，通过建立心血管和再生医学中心的机构承诺，这种情况将得到进一步改善。结合目前职业奖项的支持，这种环境将使首席调查员能够获得技术和批判性思维技能，开始一条成功的独立调查路线。

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.