Developmental Patterning of the Sinoatrial Node

描述（由申请人提供）：窦房结的心脏起搏器细胞启动并维持心脏的节律性跳动。这种功能要求起搏器细胞与工作心肌隔离，但也与之相连。虽然成熟的窦房结已被广泛研究，但对于窦房结在发育过程中是如何形成绝缘的却知之甚少。然而，了解原生起搏器细胞如何与心脏其余部分建立适当的连接，将为未来旨在纠正窦房结功能障碍和/或心律失常的药理学和细胞基础疗法提供关键见解。因此，这项为期五年的职业发展计划旨在达到两个主要目的：1)确定在发育过程中调节窦房结模式的细胞和分子机制，重点是起搏器细胞如何成为电绝缘的；2)为首席研究员Michael Bressan博士提供支持和培训，因为他从博士后研究员转变为独立研究员。具体来说，本研究将验证一个假设，即在胚胎中起搏器细胞分化后不久，TGFb/BMP介导的纤维化程序在窦房结周围启动，从而隔离并保护中央起搏器细胞免受心房肌细胞的影响。这将在三个特定目标中进行测试：a)定义产生窦房隔离的发育时间和生理/分子特性，b)确定负责这种隔离的细胞群的来源，以及c)测试TGFb和BMP对窦房结模式正确产生的要求。此外，这个拟议的项目将允许布雷桑博士扩展他目前的研究经验。在Takashi Mikawa博士的指导下，Bressan博士将探索在发育过程中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化在内的先进技术的培训。总的来说，这些研究将大大提高我们对窦房结发育的理解，同时允许Bressan博士朝着他成为独立研究员的长期目标前进。

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.