Wednesday, April 30, 2025
4/30/2025
Identification of compensatory mechanisms to rescue aortic arch artery defects - PROJECT SUMMARY The aortic arch artery and its branches are blood vessels that route the oxygenated blood from the heart to the systemic circulation. Defects in the development of the aortic arch artery lead to lethal forms of congenital heart disease (CHD) due to interruption(s) in the systemic circulation, for example, the interrupted aortic arch type B (IAA-B). These defects often occur in conjunction with 22q11 deletion syndrome, the most common congenital chromosomal abnormality syndrome in humans. Therefore, understanding genes and mechanisms regulating the development of the aortic arch artery will provide valuable insights into CHD etiology and potential treatments. Aortic arch artery and its branches form following the remodeling of the symmetrical pharyngeal arch arteries (PAAs) into the asymmetrical vascular tree. We demonstrated that the PAA endothelium is mainly derived from progenitors in the second heart field (SHF). Furthermore, we found that genetic mutations resulting in the deficiency in the SHF-derived endothelium cause IAA-B. This grant application describes two new mouse models in which an unexpected source of endothelial progenitors repairs the deficiency in the SHF- derived endothelial cells (ECs) and rescues aortic arch artery formation. Our discovery of an alternative endothelial source that repairs PAA defects has opened the possibility to determine mechanisms regulating this compensatory repair process. We also discovered that the compensatory endothelium is not recruited in the Tbx1+/- mouse model of 22q11 deletion syndrome, resulting in IAA-B and neonatal lethality in ~65% of Tbx1+/- mice. In this grant application, we propose to determine the source of compensating ECs, mechanisms regulating the recruitment of compensatory endothelium, and how Tbx1 regulates this process. To accomplish these goals, we propose the following Specific Aims: 1 To test the hypothesis that the compensating endothelium is derived from a vein, and 2 To determine signals regulating the recruitment of the compensatory ECs to rescue arch artery formation. In this proposal, we will use novel mouse strains, genetic engineering, quantitative 3D confocal imaging, in situ hybridization, and RNAseq to uncover candidate genes regulating the compensatory response. Upon completing the proposed work, we will uncover innate mechanisms of compensation and robustness, whereby a newborn's viability is ensured through alternative mechanisms. Harnessing these mechanisms would provide new opportunities for treatments of CHD in the future.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).