Calcium-mediated modulation of cardiac development

描述(由申请人提供)： 这份有导师指导的临床科学家发展奖申请书描述了为申请者提供的职业发展和培训计划，申请者已经完成了儿科住院医师和儿科心脏病学研究员学位。这个项目将在斯科特·里夫基斯博士的指导下进行，他有培养年轻的医学博士和博士培养的独立研究科学家的经验，是受体生物学领域公认的领导者。申请人打算利用他在肌肉细胞生物学和先天性心脏损伤生理学方面的专业知识，并继续他在发育分子生物学方面的培训，研究心脏发育异常的起源。 本文提出的研究计划将侧重于细胞内钙信号在控制心脏发育中的作用。钙作为细胞内信使的作用是众所周知的。初步数据表明，细胞内钙水平的变化和位于钙下游的信号级联可以显著改变心脏的发育。此外，以前的研究已经证明在哺乳动物早期心脏中存在钙调节机制。 为了进一步了解这些现象，提出了以下具体目标。(1)我将研究细胞内钙水平的降低是否影响心肌细胞分化和心脏形态发生。(2)研究CaMK II在心肌形态发生和心肌细胞分化调控中的作用。最后，(3)我将确定钙信号是否在发育中的心脏中调节TAF的表达和功能。 耶鲁大学在生物医学研究方面处于世界领先地位，儿科已证明自己是培养儿科内科科学家的理想场所。一个由耶鲁大学教职员工组成的享有盛誉的咨询委员会将在这个项目期间监督申请人的进展。结合Rivkees博士的指导，这些资源应该会让申请者发展成为一名成功的独立研究人员，并为发育心脏病学领域做出巨大贡献。

DESCRIPTION (provided by applicant): This Mentored Clinical Scientist Developmental Award application describes a program of career development and training for the applicant, who has completed a residency in pediatrics and a fellowship in pediatric cardiology. This program will be under the mentorship of Dr. Scott Rivkees, who has experience grooming young M.D. and Ph.D. trained scientists for independent research and who is a recognized leader in the field of receptor biology. The applicant intends to study the origins of abnormal heart development by using his expertise in muscle cell biology and in the physiology of congenital heart lesions and by continuing his training in developmental molecular biology. The research plan presented herein will focus on the role of intracellular calcium signals in controlling cardiac development. Calcium's role as an intracellular messenger is well-recognized. Preliminary data demonstrate that alterations in intracellular calcium levels and the signal cascades that lie downstream of calcium can dramatically alter cardiac development. In addition, previous studies have demonstrated the presence of calcium regulatory mechanisms in the early mammalian heart. To further understand these phenomena, following Specific Aims are proposed. (1) I will examine whether a reduction of intracellular calcium levels affect cardiac myocyte differentiation and cardiac morphogenesis. (2) I will examine the role of CaMK II in the regulation of cardiac morphogenesis and myocyte differentiation. Finally, (3) I will determine whether calcium signals modulate TAF expression and function in the developing heart. Yale University is a world leader in biomedical research, and the Department of Pediatrics has proven itself to be an ideal setting to train pediatric physician-scientists. A prestigious advisory committee drawn from the faculty at Yale will monitor the applicant's progress during this project. Combined with Dr. Rivkees mentorship, these resources should allow the applicant to develop into a successful independent investigator and make great contributions to the field of developmental cardiology.