Genetic and Molecular Analysis of Mutants with Congenital Heart Defects

先天性心脏缺陷突变体的遗传和分子分析

• 批准号: 8494674
• 负责人: Ivan Paul Moskowitz
• 金额: $ 36.25万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8494674
• 关键词: Atrial Heart Septal Defects; Cardiac; Carrier Proteins; Cells; Complement; Congenital Heart Defects; Defect; Development; Embryo; Erinaceidae; Event; Genes; Genetic; Goals; Grant; Growth; Heart; Heart Atrium; Heart Septal Defects; Human; Laboratories; Light; Maps; Molecular; Molecular Analysis; Mutant Strains Mice; Mutation; Pathway interactions; Phenotype; Positioning Attribute; Proteins; Pulmonary Circulation; Reagent; Role; Signal Transduction; Specific qualifier value; Stem cells; Transgenic Organisms; Work; base; body system; congenital heart disorder; genetic analysis; mutant; novel; positional cloning; progenitor; smoothened signaling pathway; transcription factor

Project Summary Atrial septation is a critical step in separating the systemic and pulmonary circulations in tetrapods and atrial septal defects are among the most common forms of human congenital heart disease (CHD). The objective of this project is to investigate the cellular and molecular mechanisms required for atrial septation and atrial septal progenitor cell specification. The canonical view of atrial septation is based on intracardiac morphogenetic events. However, recent work in our laboratory and others has engendered a novel paradigm for atrial septation, based on contributions from the second heart field (Mommersteeg et al., 2006; Snarr et al., 2007b; Goddeeris et al., 2008). We have identified a subset of cardiac progenitor cells specific for the atrial septum. Hedgehog signaling in the posterior second heart field marks atrial septal progenitors. These findings imply that atrial septum vs. non-septum cell fate is distinguished at the level of progenitor cell specification rather than by positional information acquired subsequently within the developing atrium. The molecular mechanisms by which these newly characterized progenitor cells are specified and generate the atrial septum are currently unknown. Here, we propose an integrative approach using both forward and reverse genetics to build a molecular pathway required for atrial septation and investigate the specification of atrial septal progenitors. Our specific aims are to (1) Analyze the specification, proliferation, and survival of atrial septal progenitors in wild-type and Hedgehog signaling mutant embryos; (2) Analyze atrial septal progenitors and Hh signaling in cac2 mutant mice; and (3) Identify the molecular basis of cac2, a novel gene required for atrial septation. A greater understanding of the molecular basis of atrial septal progenitor cell specification and function will be delivered at the end of the granting period. This work will contribute to an ongoing paradigm shift in our understanding of the ontogeny of cardiac septal defects.

项目总结