Regulation of cardiac morphogenesis by Nkx genes

Nkx 基因对心脏形态发生的调节

基本信息

批准号：
7807021
负责人：
KIMARA L TARGOFF
金额：
$ 12.95万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7807021
关键词：
Aborted Fetus Animal Model Biological Cardiac Cardiac Myocytes Cardiology Cell Count Cell Polarity Cell Shape Cell physiology Cells Childhood Clinical Comprehension Congenital Heart Defects Data Defect Development Embryo Embryonic Development Environment Exhibits Family Gene Components Gene Targeting Genes Genetic Genetic Determinism Heart Heart Atrium Homologous Gene Human Knowledge Laboratories Laboratory Research Lead Light Live Birth Mentors Microarray Analysis Modeling Molecular Morbidity - disease rate Morphogenesis Morphology Mus Neonatal Pathway interactions Phenotype Physicians Play Principal Investigator Process Recurrence Regulation Research Personnel Risk Role Scientist Staging Testing Training Tube Universities Validation Ventricular Zebrafish abstracting base cell motility congenital heart disorder disorder prevention gene function improved insight loss of function malformation mortality precursor cell prognostic programs transcription factor zebrafish genome

项目摘要

DESCRIPTION (provided by applicant): The Principal Investigator seeks advanced training in a mentored environment to study the regulation of cardiac morphogenesis by Nkx genes in the zebrafish embryo. In the laboratory of Dr. Deborah Yelon and with the support of the Division of Pediatric Cardiology at Columbia University, the primary objective is to provide the Principal Investigator with an environment to pursue training in formal courses and laboratory research that will enhance her development into an independent physician-scientist. The Principal Investigator will use the zebrafish model to study defects in cardiac chamber formation as a means to understand the genetic regulation of congenital heart disease (CHD). NKX2-5 is a key causative gene in human CHD and plays a critical role in normal chamber formation in mice. However, comprehension of the underlying cellular and molecular mechanisms regulated by NKX2-5 is extremely limited. Our preliminary studies suggest that loss-of-function of the zebrafish NKX2-5 homologs, nkx2.5 and nkx2.7, impairs morphogenesis of the ventricular and atrial cardiac chambers. Furthermore, we find that the first sign of abnormal cardiac morphogenesis in these embryos appears during the initial assembly of the heart: specifically, the inhibition of nkx2.5 and nkx2.7 gene function leads to the formation of an abnormally short and wide ventricular portion of the heart tube. We hypothesize that nkx genes are critical regulators of the cellular processes that drive the early stages of heart tube assembly. To test this hypothesis, we propose three specific aims: 1. To characterize the cellular mechanisms by which nkx genes regulate elongation of the developing ventricle. Through phenotypic characterization of nkx-deficient embryos, we will test the hypothesis that nkx genes guide specific aspects of proliferation, cell shape change, cell movement, and/or cell polarity during the process of ventricle assembly. 2. To define the cellular role that nkx genes play in atrial morphogenesis. Having determined the impact of nkx genes on ventricular morphogenesis, we will use similar experimental strategies to test the hypothesis that nkx genes play a parallel role during atrial assembly. 3. To identify the downstream effector genes through which nkx genes regulate heart tube assembly. Using microarray analysis and subsequent validation, annotation, and loss-of-function analysis of target genes, we will identify the components of the nkx pathway that play essential roles during the initial assembly of the heart. Together, these studies will shed new light on the cellular processes and molecular mechanisms underlying CHD. In the long term, this insight may provide us with the opportunity to generate better prognostic information, improved prediction of recurrence risk, and possible disease prevention within families with CHD. (End of Abstract)

描述（由申请人提供）：首席研究者在指导环境中寻求高级培训，以研究斑马鱼胚胎中NKX基因对心脏形态发生的调节。在Deborah Yelon博士的实验室以及哥伦比亚大学小儿心脏病学系的支持下，主要目的是为首席研究人员提供一个环境，以寻求正式课程和实验室研究的培训，以将其发展为独立的医师科学家。主要研究者将使用斑马鱼模型研究心脏腔形成中的缺陷，以了解先天性心脏病（CHD）的遗传调节的手段。 NKX2-5是人类冠心病中的关键致病基因，在小鼠正常腔形成中起关键作用。但是，对由NKX2-5调节的基本细胞和分子机制的理解非常有限。我们的初步研究表明，斑马鱼NKX2-5同源物，NKX2.5和NKX2.7的功能丧失会损害心室和心房心脏腔的形态发生。此外，我们发现这些胚胎中心脏形态发生异常的第一个迹象出现在心脏的初始组装过程中：具体来说，抑制NKX2.5和NKX2.7基因功能会导致心脏管的异常短而宽的心室部分形成。我们假设NKX基因是驱动心管组装早期阶段的细胞过程的关键调节因子。为了检验这一假设，我们提出了三个具体目的：1。表征NKX基因调节发育室伸长的细胞机制。通过NKX缺陷胚胎的表型表征，我们将检验以下假设：NKX基因在心室组装过程中指导增殖，细胞形状变化，细胞运动和/或细胞极性的特定方面。 2。定义NKX基因在心房形态发生中起的细胞作用。在确定了NKX基因对心室形态发生的影响之后，我们将使用类似的实验策略来测试NKX基因在房屋组装过程中起并行作用的假设。 3。确定NKX基因调节心脏管组件的下游效应基因。使用微阵列分析以及随后的验证，注释和目标基因的功能丧失分析，我们将确定在心脏初始组装过程中起着基本作用的NKX途径的成分。总之，这些研究将为冠心基础的细胞过程和分子机制提供新的启示。从长远来看，这种见解可能会为我们提供机会，以产生更好的预后信息，改善复发风险的预测以及CHD家庭中可能的疾病预防。（抽象的结尾）