Pulmonary arterial hypertension (PAH) in children or adults is a progressive and fatal disease characterized by sustained elevations of pulmonary artery pressure of unknown etiology. Pulmonary arterial smooth muscle cell (PASMC) and endothelial (PAEC) proliferation that ultimately lead to heart failure are key components of the pulmonary hypertension pathophysiologic response. Our current diagnostic/prognostic state of art (echocardiography, 6 minute walk test and NTproBNP levels) are not lung/vascular specific, have poor diagnostic correlation, confounded by systemic diseases and are not applicable to all ages. We now have pilot data that IGFBP dysregulation is a significant circulating predictor of PAH severity and survival. The overall goal of this proposal is to elucidate the in vitro and in vivo mechanistic role of IGF axis in PAH and potential as a circulating new measure of PAH therapeutic response and survival. The significance of the proposed studies is that by linking dysregulation of the IGF pathway to pulmonary endothelial/smooth muscle cellular proliferation, patient survival, and response to treatment, a critical mechanism of PAH pathobiology is revealed and provides the basis for new therapeutic, diagnostic and prognostic strategies in PAH. Using available pediatric (University of Colorado), adult (Vanderbilt) and multicenter (PAHBiobank) cohorts and isolated PAEC and PASMC from the PHBI, our overall goal will be addressed in the following specific aims: 1) Determine if IGF and IGFBPs are PAH predictors of severity, survival and response to therapy in children and adults. 2) Identify genetic variants associated with circulating levels of IGFs and IGFBPs and their relationship with clinical severity and survival. 3) Defining the contribution of the IGFBPs to the phenotypic responses of pulmonary vascular cells (PAEC and PASMC) from PAH and normal donors. If validated in this study, dysregulation of the IGF pathway could fill an important gap in clinical care and serve as a new opportunity for a more thorough understanding of PAH pathobiology and development of new therapeutic targets.
We propose a new study to validate IGFs and IGFBPs, as new circulating indicators of PAH severity and survival, in (Aim 1) multicenter PAH Cohorts of children (University of Colorado), adults (Vanderbilt) and PAHBiobank (Cincinnati Children's), and whether genomic variants drive IGF axis dysregulation (Aim 2) and elucidate the IGF and IGFBP mechanistic effects on cellular proliferation, signaling and cellular differentiation of pulmonary vascular cells (PAEC and PASMC) from PAH and normal donors (Aim 3) The results of this study will elucidate the in vivo clinical value of IGF axis dysregulation as a circulating new measure of PAH therapeutic response and survival, and potential new therapeutic pathway in PAH.