Self-organization of the sinoatrial nod

窦房点头的自组织

基本信息

批准号：
10638838
负责人：
Hee Cheol Cho
金额：
$ 52.36万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10638838
关键词：
Acute Aging Anti-Inflammatory Agents Architecture Area Arrhythmia Buffers Cardiac conduction system Cells Data Development Electrophysiology (science)Embryo Embryonic Development Extracellular Matrix Family suidae Fibroblasts Fibrosis Gene Delivery Generations Giant Cells Goals Heart Heart Atrium Homing Immune In Vitro Infection Inflammatory Inflammatory Response Injury Knowledge Lead Life Membrane Molecular Morphology Muscle Cells Myocardium Newborn Animals Nodal Pacemakers Pathologic Pathway interactions Patients Persons Proteins Rodent Sick Sinus Syndrome Signal Transduction Sinoatrial Node Sinus Sinus Arrhythmia Somatic Cell Somatic Gene Therapy Source Stimulus Structure System Systems Development Technology Transfer Testing Therapeutic Time Tissues Transgenic Mice Ventricular Ventricular Premature Complexes Work base cytokine heart rhythm in vivo in vivo Model insight macrophage mouse model nodal myocyte novel postnatal prevent rational design recruit self assembly self organization tool transcription factor

项目摘要

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.

项目概要/摘要窦房结（SA 节点或 SAN）是一个微小的异质结构，它启动并设定心跳的节奏。最近对胚胎发育的见解确定 T-box (TBX) 转录因子是 SAN 分化的关键决定因素。待定18，特别是，已被证明对于 SA 节点的规范是不可或缺的发展。在过去的十年中，我们已经了解了很多关于电生理学基础的知识起搏器细胞自动化。膜和 Ca2+ 时钟机制可以解释单个起搏细胞水平的自动化。然而，心律不能仅仅由单个起搏细胞自发电活动的总和。相反，窦房结的复杂结构允许<10,000个节点起搏细胞起搏- 并驱动心房心肌。然而，人们对 SAN 如何自组装知之甚少。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 节点区域实现其唯一的节奏和驱动功能。我们假设 Tbx18 诱导急性，炎症信号和急性炎症细胞因子促进归巢和/或增殖成纤维细胞和巨噬细胞等非肌细胞的形成，从而使发育中的细胞自组装 SAN。体细胞基因转移技术、体细胞重编程以及体外和体内模型电生理学是本研究的主要工具。这个提议是刻意机械化的，唯一的目标是了解同步窦性心律的分子决定因素一代。