Saturday, May 4, 2024
5/4/2024
Project Summary The goals of this proposal are to help Sasha Prisco, MD, PhD, a cardiovascular physician-scientist, transition to independence and to further the understanding of mechanisms of right ventricular dysfunction in pulmonary arterial hypertension. Pulmonary arterial hypertension is a progressive vasculopathy which increases right ventricular afterload, leading to right ventricular failure. Right ventricular function is the greatest predictor of survival in pulmonary arterial hypertension. Unfortunately, there are no current pharmacologic therapies that directly target the failing right ventricle. Our recent preclinical data demonstrated pathological inflammation through activation of the cytokine receptor glycoprotein 130 induced deleterious microtubule remodeling, downregulation of junctophilin-2 (an essential protein that maintains t-tubule structure and function), and depressed right ventricular function in pulmonary arterial hypertension. Emerging data show alterations in gut microbiota disrupt the intestinal barrier, which permits bacterial translocation, and subsequently activates systemic inflammation, suggesting that modulating the microbiome may be an approach to mitigate inflammation. We recently identified that modifying the gut microbiome with intermittent fasting improved right ventricular function and postulate that increased abundance of Lactobacillus underlies these benefits. We will test the hypothesis that Lactobacillus supplementation combats pathological gut dysbiosis, which prevents immune cell activation, and subsequent glycoprotein 130-mediated microtubule remodeling in the following specific aims. In Aim 1, we will determine if Lactobacillus supplementation mitigates pathological microtubule remodeling and enhances right ventricular function in two rodent models of pulmonary arterial hypertension, monocrotaline and Sugen-hypoxia. In Aim 2, we will investigate the effects of Lactobacillus supplementation on gut dysbiosis and systemic inflammation. For this proposal, we will use a variety of approaches from metagenomics analysis of the gut microbiome, SomaScan proteomics, and single-cell RNA-sequencing to histological assessments, echocardiography, invasive hemodynamics, and treadmill exercise testing. This project has the potential to identify a novel therapeutic approach for pulmonary arterial hypertension.
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).
