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 are key components of the pulmonary hypertension pathophysiologic response. Although the number of vasodilator drugs has increased, still 20-30% of patients do not respond and non-responders have a poor prognosis eventually requiring lung transplantation1-4. 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. In essence, we lack simple, minimally invasive more lung/vascular specific, objective, repeatable, generalizable and less expensive measures of PAH to improve outcomes. We now have pilot data that the pulmonary angiogenic protein, hepatoma derived growth factor (HDGF), 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 HDGF 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 HDGF to pulmonary endothelial/smooth muscle cellular proliferation, patient survival, and response to treatment, a critical step in the function of HDGF 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 HDGF is a PAH predictor of severity, survival and response to therapy in children and adults. 2) Determine if circulating HDGF levels are affected by specific FPAH gene defects and in unaffected carriers, and determine if human HDGF genomic variants are associated with IPAH. 3) Defining the contribution of HDGF to the phenotypic responses of pulmonary vascular cells (PAEC and PASMC) from PAH and normal donors. If validated in this study, HDGF could fill an important gap in the current clinical care and treatment of PAH patients for improved risk stratification, assessment of response to therapy, clinical worsening exceeding current clinical care measures.
We propose a new study to validate HDGF, a new circulating indicator of PAH severity and survival, in (Aim 1) multicenter PAH Cohorts of children (University of Colorado), adults (Vanderbilt) and PAHBiobank (Cincinnati Children?s), in unaffected FPAH carriers and the presence of HDGF genomic variants in IPAH (Aim 2) and define the contribution of HDGF to the phenotypic responses 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 HDGF as a circulating new measure of PAH therapeutic response and survival, and in vitro, the mechanistic role of HDGF in PAH.
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