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.
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