Self-organization of the sinoatrial nod

项目摘要/摘要 窦房结(窦房结或窦房结)是一种微小的、异质的结构，它起始于 并设定心跳的节奏。对胚胎发育的最新见解已经 精确定位的T-box(TBX)转录因子是SAN分化的关键决定因素。Tbx18， 特别是，已经被证明对于SA节点的规范来说是不可或缺的 发展。在过去的十年里，我们已经学到了很多关于电生理学的基础 起搏细胞自律性。膜和钙的时钟机制可以解释 在单个起搏器细胞水平上的自动化。然而，心脏节律不能仅仅由 单个起搏器细胞自发电活动的总和。相反， 窦房结复杂的结构使10,000个结节起搏器细胞能够起搏- 和-驱动心房心肌。然而，人们对存储区域网络如何自组装知之甚少 它的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心肌细胞网络被限制在SA结区 以实现其唯一的速度和驾驶功能。我们假设TBX18会引起急性， 炎症信号和急性炎症细胞因子促进归巢和/或增殖 非肌细胞，如成纤维细胞和巨噬细胞，从而自组装发育中的 山姆。体细胞基因转移技术、体细胞重编程和体内外模型 电生理学是本研究的主要工具。这个提议是故意机械化的， 唯一的目标是了解同步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.