Developmental Patterning of the Sinoatrial Node

窦房结的发育模式

• 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
• 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

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）：Sinoatrial节点的心脏起搏器细胞启动并保持心脏的节奏跳动。此功能要求将起搏器细胞与工作心肌隔离，但也与工作心肌连接。尽管已经对成熟的辛里氏节点进行了广泛的研究，但关于如何在发育过程中对窦节点绝缘材料的图案却鲜为人知。然而，了解天然起搏器细胞如何建立与心脏其余部分的正确连通性，将为未来的药理学和细胞基于核心疾病的基于药理和细胞的疗法提供关键的见解。因此，这项五年的职业发展计划旨在实现两个原则：1）确定在开发过程中调节Sinoatrial节点模式的细胞和分子机制，重点是Pacemaker细胞如何进行电源性隔离，而2）为主要研究者提供支持和培训，以使他的迈克尔·布雷斯（Michael Bressan）博士从独立的研究人员中转移到独立研究人员中，以实现迈克尔·布雷斯（Michael Bressan）博士。具体而言，该提案将检验以下假设：在胚胎中起搏器细胞分化后不久，TGFB/BMP介导的纤维化程序会在Sinoatrial节点外围启动，进而保护并保护中枢性调味细胞免受心脏肌细胞的影响。这将以三个特定目的进行测试，这些特定目标将a）定义产生正弦绝缘材料的发育时机和生理/分子特性，b）确定负责这种绝缘材料的细胞群的来源；以及c）测试TGFB和BMP的需求，以适当地产生这种悬体node node dotting。此外，这个提议的项目将使布雷森博士能够扩大他当前的研究经验。在高田博士的指示下，布雷桑博士将探索在渐进发育阶段调节窦淋巴结图案的生理和分子机制，并通过提前培训，包括逆转录病毒介导的体细胞生物。总的来说，这些研究将大大提高我们对辛里斯节点开发的理解，同时允许布雷桑博士朝着成为独立研究人员的长期目标迈进。