Pulmonary hypertension (PH) is a progressive disease leading to right heart failure and death. Despite advances indicating that PH would be best described as a systemic disease, PH continues to be treated primarily as a disease of pulmonary vasculature with most current therapies targeting pulmonary endothelial dysfunction, vascular smooth muscle proliferation and vasoconstriction. Therefore, development of drug treatments with alternate targets may benefit patients by providing more specific therapies and better outcomes. Our published and preliminary studies have shown increased activated microglia and neuroinflammation in autonomic brain regions, particularly the paraventricular nucleus of the hypothalamus, with PH. Interestingly, most of these microglia are bone marrow (BM)-derived. This led us to propose the hypothesis that dysfunctional brain-BM interactions lead to neuroinflammation resulting in development and establishment of PH. Two aims are planned to evaluate this: Aim 1 will use multiple animal models of PH to evaluate the hypothesis that neuroinflammation and migration of BM cells play critical roles in the development and establishment of PH. Aim 2 will investigate the hypothesis that microglia express distinctive gene profiles during PH, and will compare profiles of resident vs. BM-derived microglia.BM chimeric rats will be generated and after full recovery, PH induced in rats with 60 mg/kg monocrotaline with 4 different endpoints or with weekly injections of SU5416 (20 mg/kg/dose, or vehicle) and chronic hypoxia (10%O2) for 3 weeks (n=10/group) in mice. At endpoint, right ventricular systolic pressure (RVSP) will be determined by Millar catheterization followed by collection of brain, heart and lungs for analysis. Also, to expand on our preliminary data, a time-course of the relationship between RVSP, microglia and sympathetic activity will be constructed, with phenotyping of neuro-microglia interactions by immunostaining neurons to evaluate the roles of resident and BM-derived microglia. Furthermore, gene profiles of microglia will be determined in BM-chimeric rats with and without PH by single cell RNAseq.We expect results of these studies to contribute to better understanding of the role of microglia and BM-derived cells in the pathophysiology of PH. Moreover, identification of specific genes and pathways and their interactions with neuronal phenotypes will likely unmask new potential targets for PH therapy.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|