Pulmonary arterial hypertension (PAH) is a devastating syndrome, particularly for patients with systemic sclerosis (SSc), leading almost uniformly to death through right ventricular (RV) failure. We hypothesize that the severity of structural changes involving the pulmonary vasculature (PV) and the RV, resulting in severe RV-PV dysfunction, accounts for diverging responses to therapy and an overall worse outcome in SSc-related PAH (PAH-SSc) as compared to idiopathic PAH (IPAH). Little is known about genetic and phenotypic characteristics that might predict the development of PAH, RV-PV dysfunction, response to therapy, and survival in patients with PAH-SSc. The objectives of this SCCOR project are to (i) develop reliable measures of RV-PV function, (ii) characterize patterns of gene expression and identify candidate gene polymorphisms associated with susceptibility to PAH in SSc, and (iii) use these tools to guide therapy aimed at RV-PV dysfunction in PAH-SSc.
In Specific Aim #1, we will characterize optimal measures of RV-PV function by hemodynamic, echo-cardiographic, and Magnetic Resonance Imaging profiles in well- phenotyped patients with PAH-SSc, which will complement specific measurements of RV-PV uncoupling in Project #2.
In Specific Aim #2, we will employ high throughput genomic technologies to examine the patterns of gene expression, which explain susceptibility to PAH in subsets of patients with SSc from this project and Project 3. Patterns of expression analyzed within each clinical condition will allow us to determine both concordantly and discordantly regulated gene clusters, link these gene clusters with functional measurements developed in Specific Aim #1, and determine modifier gene profiles associated with PAH-SSc. From these expression studies and those in Projects 4 and 5 we will prioritize novel PAH candidate genes.
Specific Aim #3 will test the effects of selected therapies on RV-PV function in PAH-SSc patients and other biomarkers identified in Aims #1 and #2.
In Specific Aim #4, we will establish biological validation of prioritized PAH candidate genes via mid- and high-throughput genotyping of DNA procured from a large group (N=1,000) of extensively characterized patients with PAH-SSc (Aim #1), SSc without PAH (Project #3), IPAH, and healthy controls. We will test for association between select variants/haplotypes in candidate genes and susceptibility of PAH in this group and a replicate group of African-Americans. Completion of these studies will provide invaluable information that will guide future mechanistic and clinical studies designed to improve clinical outcomes in PAH-SSc.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZHL1)
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Johns Hopkins University
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