Self-organization of the sinoatrial nod

项目概要/摘要 窦房结（SA结或SAN）是一个微小的异质结构， 设定心跳的节奏。对胚胎发育的最新见解 T-box（TBX）转录因子是SAN分化的关键决定因素。Tbx18， 特别是，已经被证明是必不可少的规范的SA节点期间， 发展在过去的十年里，我们已经了解了很多关于电生理基础的 起搏细胞自律性膜和Ca 2+时钟机制可以解释 自律性在单个起搏细胞水平。然而，心律不能仅仅由 单个起搏细胞自发电活动的总和。而是 复杂的窦房结结构允许<10，000个节点起搏细胞起搏- 驱动心房心肌然而，人们对SAN如何进行自组装知之甚少 其结构和同步窦性心律的分子决定因素;即，如何 起搏细胞和丰富的非肌细胞网络被限制在SA结区域 来实现它唯一的速度驱动功能。我们假设Tbx 18诱导急性， 炎性信号和急性炎性细胞因子促进归巢和/或增殖 的非肌细胞，如成纤维细胞和巨噬细胞，从而自我组装的发展 San.体细胞基因转移技术、体细胞重编程及体内外模型 是本研究的主要工具。这一建议是故意机械化的， 唯一的目标是了解同步性窦性心律的分子决定因素 一代

Project Summary/Abstract The sinoatrial node (SA node or SAN) is a minuscule, heterogeneous structure which initiates and sets the rhythm of the heartbeat. Recent insights into embryonic development have pinpointed T-box (TBX) transcription factors as key determinants of the SAN differentiation. Tbx18, in particular, has been shown to be indispensable for the specification of the SA node during development. In the past decade, we have learnt much about the electrophysiological bases of pacemaker cell automaticity. The membrane and Ca2+ clock mechanisms can explain the automaticity at the single, pacemaker cell level. However, heart rhythm cannot arise from mere summation of the spontaneous electrical activities from single pacemaker cells. Rather, the intricate architecture of the sinoatrial node allows the <10,000 nodal pacemaker cells to pace- and-drive the atrial myocardium. However, little is known about how the SAN can self-assemble its structure and the molecular determinants of synchronous sinus rhythm; i.e., how the pacemaker cells and the rich network of non-myocytes become confined into the SA node area to achieve its sole function of pace-and-drive. We hypothesize that Tbx18 induces acute, inflammatory signals, and the acute inflammatory cytokines facilitate homing and/or proliferation of non-myocytes such as fibroblasts and macrophages, and thus self-assembly of the developing SAN. Somatic gene transfer technology, somatic cell reprogramming, and in vitro & in vivo models of electrophysiology are the main tools of this study. This proposal is deliberately mechanistic, with the singular goal of understanding the molecular determinants of synchronous sinus rhythm generation.