Regulation of cardiac morphogenesis by Nkx genes in the zebrafish embryo

斑马鱼胚胎中 Nkx 基因对心脏形态发生的调节

• 批准号: 7392343
• 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
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392343
• 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; Disruption; 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; size; transcription factor; zebrafish genome

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)

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