Regulation of cardiac chamber morphogenesis in zebrafish

斑马鱼心室形态发生的调节

• 批准号: 6970395
• 负责人: DEBORAH YELON
• 金额: $ 38.03万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6970395
• 关键词: alternatives to animals in research; cardiac myocytes; cardiogenesis; cell biology; cell cell interaction; cell growth regulation; cell migration; cell morphology; endocardium; genetic mapping; heart ventricle; hemodynamics; histogenesis; in situ hybridization; molecular biology; molecular cloning; transmission electron microscopy; zebrafish

DESCRIPTION (provided by applicant): The embryonic vertebrate heart is composed of 2 major chambers, a ventricle and an atrium, each with a characteristic morphology that defines its functional capacity. Congenital heart defects are often associated with dysmorphic cardiac chambers, but the regulation of cardiac chamber morphogenesis is not well understood. Cardiac chamber morphogenesis can be divided into 2 major phases: heart tube assembly, in which bilateral precursor populations unite to form a tube, and chamber emergence, in which this simple cylinder transforms into a series of morphologically discrete chambers. The long-term goal of our research is to identify the cellular and molecular mechanisms that regulate these 2 phases of chamber morphogenesis. Using the zebrafish as a model organism, we can combine embryologic and genetic approaches, using high-resolution live imaging to determine how key genes influence cardiomyocyte behavior. Our preliminary time-lapse analyses of heart tube assembly suggest that this process is driven by multiple genes that collaborate to regulate regional differences in directed cardiomyocyte movements. Additionally, our initial morphometric analyses of chamber emergence suggest that this process is governed. by both intrinsic and extrinsic factors that control regional changes in cardiomyocyte morphology. Finally, our recent studies of novel mutations suggest that the slow fuse and change of heart genes are critical regulators of heart tube assembly and chamber emergence, respectively. Building on this foundation, we propose to test (1) how cardiomyocyte movements are regulated by a critical mass of cells, formation of polarized epithelia, interactions with endoderm and endocardium, and slow fuse function, and (2) how cardiomyocyte morphology is regulated by hemodynamics, sarcomere integrity, interactions with the endocardium, and change of heart function. Together, these studies will reveal essential regulatory mechanisms of cardiogenesis and also enrich our understanding of general paradigms for organ formation.

描述(申请人提供)：胚胎脊椎动物心脏由两个主要腔室、一个脑室和一个心房组成，每个腔室都有定义其功能能力的特征形态。先天性心脏病常与心腔畸形有关，但心腔形态发生的调节尚不清楚。心腔的形态发生可分为两个主要阶段：心管组装阶段和心腔出现阶段，心管组装阶段的两侧前体群体结合形成一个管状结构；心腔形成阶段，这个简单的圆柱体转变为一系列形态离散的腔室。我们研究的长期目标是确定调节这两个腔体形态发生的细胞和分子机制。利用斑马鱼作为模式生物，我们可以结合胚胎学和遗传学的方法，使用高分辨率的实时成像来确定关键基因如何影响心肌细胞的行为。我们对心管组装的初步延时分析表明，这一过程是由多个基因共同驱动的，这些基因共同调节定向心肌细胞运动的区域差异。此外，我们对腔室出现的初步形态计量学分析表明，这一过程是受控制的。由控制心肌细胞形态局部变化的内在和外在因素共同作用。最后，我们最近对新突变的研究表明，心脏基因的缓慢融合和变化分别是心管组装和心腔出现的关键调节因素。在此基础上，我们建议测试(1)心肌细胞运动如何受到临界细胞质量、极化上皮的形成、与内胚层和心内膜的相互作用以及慢融合功能的调节，以及(2)心肌细胞的形态如何受到血流动力学、肌节完整性、与心内膜的相互作用和心功能的变化的调节。总之，这些研究将揭示心脏发生的基本调控机制，并丰富我们对器官形成的一般范式的理解。