TRANSCRIPTIONAL CONTROL OF CARDIAC GROWTH

心脏生长的转录控制

• 批准号: 8167794
• 负责人: Kyu-Ho Lee
• 金额: $ 19.73万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167794
• 关键词: Affect; Alleles; Anatomy; Anterior; Aorta; Atrial Heart Septal Defects; Cardiac; Cardiac Myocytes; Cells; Complex; Computer Retrieval of Information on Scientific Projects Database; Coronary artery; Defect; Development; Dose; Event; Funding; Gene Targeting; Genes; Grant; Growth; Heart; Human; Institution; Missense Mutation; Modeling; Molecular; Mus; Newborn Infant; Pathway interactions; Program Development; Proteins; Pulmonary artery structure; Regulation; Research; Research Personnel; Resources; Right ventricular structure; Source; Stem cells; Structure; Transcriptional Regulation; Transgenic Organisms; Undifferentiated; United States National Institutes of Health; Work; congenital heart disorder; malformation; molecular marker; mouse model; null mutation; precursor cell; progenitor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Congenital heart disease (CHD) affects 0.5% of newborns each year, and approximately 1/3 of these defects are outflow tract (OFT) defects affecting proper formation of the great arteries of the heart, the aorta and the pulmonary artery. There are several models in mouse of congenital heart disease. However, these models provide an incomplete understanding of pathological events because few molecular markers sufficiently detail OFT anatomy during development from progenitors in the Second or Anterior Heart field (SHF), a dedicated pool of undifferentiated cardiac precursor cells selectively giving rise to the aortic pole of the heart, i.e. OFT and right ventricle (RV). Dr. Lee's lab is studying the regulation of the critical cardiac gene Nkx2.5. Null mutation of Nkx2.5 in mouse models results in severe hypoplasia of aortic pole constituents, likely due to dysregulation of the differentation and/or proliferative expansion of SHF progenitor cells. Other hypomorphic alleles of mouse Nkx2.5 which express varying levels of the Nkx2.5 gene product evince a dose-dependent spectrum of aortic pole-related defects, and hypomorphic missense mutation of the Nkx2.5 gene in humans is frequently implicated in OFT malformations, atrial septal defects and conduction delay, all involving cardiac structures derived from the SHF in mouse models. Making use of transgenic markers that selectively identify aortic pole precursors and downstream descendant cardiomyocytes of the OFT and RV, Dr. Lee's lab is working to characaterize the critical regulation of Nkx2.5 expression levels in cells of the SHF and aortic pole, both to better understand gene relationships in the normal cardiac development program operating in the SHF, and to identify molecular pathways whose constituent alleles may constitute modifier loci contributing to complex or multigene OFT CHD. A second effort is focused on defining the direct downstream gene targets of the Nkx2.5 gene product, which operates as a transcriptional regulator of other cardiac genes. These efforts will similarly define Nkx2.5's place in the network of genes controlling normal OFT development and dysregulated in OFT CHD entities.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 先天性心脏病（CHD）每年影响0.5％的新生儿，其中大约1/3是流出道（OFT）缺陷，影响了心脏，主动脉和肺动脉的正确形成的正确形成。先天性心脏病小鼠中有几种模型。然而，这些模型对病理事件提供了不完全的理解，因为很少有分子标记在第二或前心脏场（SHF）的发育过程中足够细节解剖结构（SHF），这是一个专用的未分化心脏前体细胞的池，可选择性地产生心脏主动脉极的主动脉极（即oft and right feltricle（rv））。 Lee博士实验室正在研究关键心脏基因NKX2.5的调节。小鼠模型中NKX2.5的无效突变导致主动脉杆成分的严重发育不全，这可能是由于SHF祖细胞的分化和/或增生性扩张的失调所致。小鼠NKX2.5的其他近似等位基因表达不同水平的NKX2.5基因产物表明了与主动脉杆相关缺陷的剂量相关的频谱，并且在人体中造成了损坏和渗透的延迟，散布了人类的nkx2.5基因的NKX2.5基因的Nkx2.5基因的差异。利用转基因标记，这些标志物有选择地识别OFT和RV的主管极前体和下游后代心肌细胞，Lee博士的实验室正在努力使SHF和主动脉群体中的NKX2.5表达水平的关键调节，以便在SHF和主动脉群体中识别shfor comant pather的所有群体中的基因之间的关系，以更好地识别shf的基因关系，该量构成了shf的正常基因群体，其群体构成了群落的基因关系。改良剂基因座有助于复杂或多基因的冠心病。第二次努力集中在定义NKX2.5基因产物的直接下游基因靶标，该基因产物是其他心脏基因的转录调节剂。这些努力将类似地定义NKX2.5在控制正常开发并在OFT CHD实体中失调的基因网络中的位置。