Thursday, November 28, 2024
11/28/2024
Approximately 1% of children are born with a congenital heart defect, with half requiring medical and/or surgical treatment. Children born with congenital heart defects that result in increased PBF develop abnormal pulmonary vascular reactivity. Although survival for these children has improved they continue to suffer morbidity and late mortality. This is due to the fact that they are at great risk for developing pulmonary vascular disease. In fact, even early pulmonary endothelial dysfunction, with abnormal vascular reactivity, causes significant morbidity and mortality. Using an experimental lamb model of CHD with increased PBF (Shunt) we were the first to identify that decreased interactions between heat shock protein 90 (hsp90) and endothelial NO synthase (eNOS) plays a major role in the reduced nitric oxide (NO) signaling associated with this disease. Our data implicate decreases in hsp90 activity as well as an increase in eNOS nitration in this process. In addition, our published data indicate that the loss of hsp90 activity correlates with the disruption of the eNOS dimeric structure. Based on these data, the overall hypothesis we will test is that eNOS nitration disrupts its interaction with hsp90 leading to dimer disruption and decreased NO generation. Further, we will investigate if stimulating hsp90 activity will restore NO signaling and endothelial function. Our investigations will be carried out in three interrelated, but independent, Aims. We will utilize a translational approach that will integrate biophysical, cellular and whole animal studies. The successful completion of our studies should yield new mechanistic insights and will identify new targets that are amenable to therapeutic intervention.
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).
