Myocardium and Conduction System from ESCs

描述（由申请人提供）： 该提案的主要目标是培养主要研究者成为心脏干细胞和再生生物学领域的独立医生科学家。 他提出了一个详细的职业发展计划和一个研究计划，涉及人类胚胎干细胞（hESC）衍生的心肌细胞。 培训计划包括课程，会议，专业指导，并形成一个咨询委员会，以促进职业发展作为一个医生，科学家。 在初步的实验中，我们证明了移植hESC衍生的心肌细胞到免疫缺陷大鼠的未损伤和梗死的心脏在体内产生人类心肌。 平行的体外工作已经确定了非常有前途的策略，用于获得丰富的培养人胚胎心肌细胞。 候选人利用这项工作提出的机会，提出了以下具体目标：1）优化hESC衍生心肌在梗死大鼠心脏中的植入，并确定这是否导致机械功能的改善; 2）测试hESC衍生心肌细胞移植物将显示与相邻宿主心肌的机电耦合的假设; 3）测试以下假设：随着体内成熟，移植的hESC衍生的心肌将显示兴奋-收缩偶联的表型改变;和4）开发用于从hESC衍生的心肌细胞纯化和/或诱导分化特化心脏传导系统细胞的策略。 华盛顿大学为此类研究和医生-科学家的发展提供了出色的环境，通过建立心血管与再生医学中心的机构承诺，这种情况将得到进一步加强。 结合目前的职业奖的支持，这种环境将使主要调查员获得技术和批判性思维技能，开始一个成功的独立调查线。

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.