Developmental Patterning of the Sinoatrial Node

窦房结的发育模式

基本信息

批准号：
8842196
负责人：
Michael C Bressan
金额：
$ 9.52万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2015-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8842196
关键词：
Ablation Action Potentials Address Adopted Architecture Arrhythmia Artificial cardiac pacemaker BMP2 gene Biological Cardiac Cell Differentiation process Cells Characteristics Chimera organism Coupled Cues Deposition Development Disease Embryo Extracellular Matrix Failure Fibroblasts Fibrosis Functional disorder Future Gene Transfer Techniques Generations Genetic Goals Heart Heart Atrium Heterogeneity Image In Situ Hybridization In Vitro Instruction Intervention Investigation Ion Channel Label Lead Life Maps Mediating Mesenchymal Mesoderm Molecular Morbidity - disease rate Morphogenesis Muscle Cells Myocardial Contraction Myocardium Nodal Pacemakers Pathway interactions Pattern Peripheral Physiological Population Postdoctoral Fellow Process Property Quail RNA Recruitment Activity Research Research Personnel Signal Transduction Sinoatrial Node Site Slice Source Specific qualifier value Staging Structure Techniques Testing Therapeutic Time Tissue Engineering Tissues Training Training Support United States Work Workload base career development design experience in vivo insight mortality nodal myocyte programs retroviral-mediated

项目摘要

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.

描述（由申请人提供）：窦房结的心脏起搏细胞启动并维持心脏的节律性跳动。该功能要求起搏细胞与工作心肌绝缘，但也与其相连。虽然成熟的窦房结已被广泛研究，但对于窦房结绝缘在发育过程中如何形成模式却知之甚少。然而，了解天然起搏细胞如何与心脏的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/或心律失常的基于药理学和细胞的疗法提供重要的见解。因此，这个五年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，重点是起搏器细胞如何变得电绝缘，2）提供支持和为首席研究员 Michael Bressan 博士提供培训，帮助他从博士后研究员转变为独立研究员。具体来说，该提案将检验以下假设：胚胎中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，从而将中央起搏细胞与心房肌细胞隔离并保护。这将在三个具体目标中进行测试，这将a）定义产生窦房绝缘的发育时间和生理/分子特性，b）确定负责这种绝缘的细胞群的来源，以及c）测试以下要求TGFb 和 BMP 用于正确生成该窦房结模式。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 Takashi Mikawa 博士的指导下，Bressan 博士将探索在渐进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先进技术培训。总的来说，这些研究将显着增进我们对窦房结发育的理解，同时使 Bressan 博士能够朝着成为独立研究员的长期目标迈进。