RASA3 is a Candidate Gene in the Pathogenesis of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare disease with poor long-term survival and no targeted therapies available. Prior studies have established that pulmonary artery endothelial cell (PAEC) injury and dysfunction, including abnormal proliferation, angiogenesis and apoptosis resistance, plays a critical role in the pathogenesis of disease. My long-term goal is to identify new molecules that may become therapeutic targets to treat and improve the lives of patients with PAH. RASA3, a GTPase activating protein, is a negative regulator of Rap1 and R-Ras, GTPases that regulate angiogenesis, endothelial cell adhesion and turnover, processes highly relevant to PAH. Previous in vitro studies have shown that RASA3 leads to dysregulation in pathways and processes highly relevant to pulmonary hypertension. I have found that RASA3 expression is decreased in four large cohorts of individuals with pulmonary hypertension (PH), and correlates with increased mortality in a cohort of individuals with sickle cell disease-associated PH. I have identified a single nucleotide polymorphism (SNP) within the RASA3 gene, rs9525228, that correlates with increased PH severity within four PH cohorts and is located at a predicted estrogen receptor-α and glucocorticoid binding site. We have also developed a conditional endothelial cell RASA3 knockout mouse for in vivo studies. The specific objective of the proposed research is to investigate the role of RASA3 in maintaining PAEC health in vitro and in vivo within the context of pulmonary vascular disease. I hypothesize that RASA3 is a critical regulator of homeostatic responses in PAEC. This hypothesis will be tested by investigating the following Specific Aims: AIM 1. Identify how RASA3-mediated regulation of BMPR2 impacts pulmonary vascular dysfunction in PAEC. My working hypothesis is that loss of RASA3 leads to dysregulated PAEC homeostasis through hyperactivation of Rap1 signaling altering cytoskeletal dynamics and resulting in BMPR2 downregulation. AIM 2. Determine the effects of RASA3 SNP rs9525228 on a PH-relevant phenotype in PAEC. My working hypothesis is that rs9525228 leads to decreased RASA3 expression. AIM 3. Determine the endothelial-specific role of RASA3 expression in the development of experimental pulmonary hypertension. My working hypothesis is that RASA3 mediates pulmonary vascular health at a proliferative, angiogenic and cell survival level. Upon completion of the proposed studies, I anticipate that my findings will delineate how loss of RASA3 expression leads to PAEC dysfunction and pulmonary vascular remodeling and establish RASA3 as a therapeutic target in PAH. Project Number: 1K08HL179459-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Clare Prohaska | Institution: INDIANA UNIVERSITY INDIANAPOLIS, INDIANAPOLIS, IN | Award Amount: $156,416 | Activity Code: K08 | Study Section: NHLBI Mentored Clinical and Basic Science Study Section[MCBS (JA)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K08HL17945901