Developmental Patterning of the Sinoatrial Node

描述(申请人提供)：窦房结的心脏起搏细胞启动和维持心脏的有节奏的跳动。这一功能要求起搏细胞与工作心肌绝缘，但也要连接到工作心肌。虽然成熟的窦房结已经被广泛研究，但关于窦房结在发育过程中如何隔绝的知之甚少。然而，了解自然起搏细胞如何建立与心脏其余部分的适当连接，将为未来旨在纠正窦房结功能障碍和/或心律失常的药物和基于细胞的治疗提供重要的见解。因此，这个为期五年的职业发展计划旨在服务于两个主要目的：1)确定在发育过程中调节窦房结模式的细胞和分子机制，重点是起搏细胞如何成为电绝缘的；2)在首席研究员Michael Bressan博士从博士后过渡到独立研究员的过程中，为他提供支持和培训。具体地说，这一提议将检验这样的假设，即在胚胎起搏细胞分化后不久，TGFb/BMP介导的纤维化程序在窦房结周围启动，进而隔离和保护中央起搏细胞免受心房肌细胞的影响。这将在三个具体目标中进行测试，这将a)确定产生窦房隔绝的发育时机和生理/分子特性，b)确定负责这种隔绝的细胞群体的来源(S)，以及c)测试适当地产生这种窦房结模式所需的转化生长因子b和骨形态发生蛋白。此外，这个拟议的项目将使布雷桑博士能够扩展他目前的研究经验。在Makashi Mikawa博士的指导下，Bressan博士将探索在进行性发育阶段调节窦房结模式的生理和分子机制，并接受包括逆转录病毒介导的体细胞转基因在内的高级技术培训。总的来说，这些研究将极大地促进我们对窦房结发育的了解，同时使布雷桑博士朝着成为一名独立研究人员的长期目标迈进。

DESCRIPTION (provided by applicant): Cardiac pacemaker cells of the sinoatrial node initiate and maintain the rhythmic beating of the heart. This function requires that pacemaker cells be insulated from, but also connected to, the working myocardium. While the mature sinoatrial node has been extensively studied, little is known regarding how sinoatrial node insulation is patterned during development. Understanding of how native pacemaker cells establish proper connectivity to the remainder of the heart, however, will provide critical insight for future pharmacological and cellular based therapies aimed at correcting sinoatrial node dysfunction and/or arrhythmic disorders. Therefore, this five year career development program is designed to serve two principle purposes: 1) to determine the cellular and molecular mechanisms that regulate sinoatrial node patterning during development, with emphasis on how pacemaker cells become electrogenically insulated, and 2) to provided support and training for the principle investigator, Dr. Michael Bressan, as he transitions from a postdoctoral fellow to an independent researcher. Specifically, this proposal will test the hypothesis that shortly after pacemaker cell differentiation in the embryo, a TGFb/BMP mediated fibrotic program initiates at the sinoatrial node periphery, which in turn insulates and protects central pacemaking cells from atrial myocytes. This will be tested in three specific aims which will a) define the developmental timing and physiological/molecular properties that generate sinoatrial insulation, b) determine the source(s) of the cell population responsible for this insulation, and c) test the requirement of TGFb and BMP for proper generation of this sinoatrial node patterning. Furthermore, this proposed project will allow Dr. Bressan to expand on his current research experience. Under the instruction of Dr. Takashi Mikawa, Dr. Bressan will explore the physiological and molecular mechanisms regulating sinoatrial node patterning at progressive developmental stages and be trained in advance techniques including retroviral mediated somatic transgenesis. Collectively, these studies will significantly advance our understanding of sinoatrial node development, while simultaneously allowing for Dr. Bressan to progress towards his long-term goal of becoming an independent researcher.