Impact of Sleep Disturbance and Circadian Disruption on Pulmonary Arterial Hypertension

Project Summary Pulmonary Arterial Hypertension (PAH) is a disease characterized by pulmonary vascular remodeling leading to right heart failure, and death. PAH is defined as a mean pulmonary arterial pressure greater than 20 mmHg at rest, as assessed by right heart catheterization. Despite advances in our understanding of PAH pathology and therapeutic interventions, the survival rate is still considerably low, with poor prognosis. Thus, there is an urgent need to find novel factors that may contribute to PAH pathogenesis and progression. Evidence has implicated sleep disturbance as a risk factor for cardiovascular diseases. However, the effects of sleep disturbance on PAH pathology are limited in the literature. Thus, this project seeks to investigate the impacts of sleep disturbance on PAH in human pulmonary vascular cells and in different mouse models of PAH. Knowledge from this study will better inform clinicians on whether to include poor sleep as an important factor in risk-stratifying PAH patients. Additionally, findings from this project may open new therapeutic windows for pulmonary hypertension by developing small molecules to manipulate the molecular clock and therefore improve the related quality of health of PAH patients. I hypothesize that sleep disturbance impairs pulmonary vascular cell phenotypes, increases the hemodynamic burden, and exacerbates PAH in mouse models of PAH. This hypothesis will be tested under two specific aims. Aim 1 determines the circadian clock oscillations in pulmonary vascular cells from healthy and PAH-diseased patients and examines the effects of clock genes on cell cycle dynamics and pulmonary vascular cells functions. To accomplish this aim, qPCR, immunoblotting, proliferation, migration and Bioluminescence assays will be performed. Aim 2 investigates whether sleep disturbance affects PAH severity and progression by using two models of sleep disturbance (sleep fragmentation and chronic jet lag), genetically predisposed mouse models of PAH (Egln1 KO, IL-6 transgenic, and Bmpr2 mutant mice), as well as Bmal1 KO mice to investigate the role of clock genes in PAH. Magnetic Resonance Imaging, cardiac hemodynamics, morphometric, histological, and molecular profiling will determine whether sleep disturbance exacerbates and/or accelerates PAH. Using integrated but independent approaches, this proposal will dissect the effects and mechanisms of poor sleep on PAH, and thus make advances in understanding and treating PAH. This project is driven by a unique and comprehensive training plan designed to integrate expertise in molecular techniques, circadian biology, sleep medicine and advanced hemodynamic measurements in cardiopulmonary disease. It emphasizes the development of technical, professional and communication skills, as well as grantsmanship and undergraduate mentorship. This proposal is supported by a sponsor (Dr. Sassi) and co-sponsor (Dr. Gourdie) whose labs have expertise in in vitro and in vivo models of cardiovascular diseases. Therefore, the project will be conducted in an ideal environment to study the impact of sleep disturbance on pulmonary arterial hypertension.