Modifying Genes in Pulmonary Hypertension

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DESCRIPTION (provided by applicant): The goal of this K08 Mentored Career Development Award is to evaluate genetic influences in the development of pulmonary and arterial hypertension (PAH), a progressive disease characterized by an elevation in the mean pulmonary artery pressure, right heart failure, and death. This goal is based on the sobering observation that despite intensive investigation, the natural progression and the molecular mechanisms underlying the development of severe pulmonary hypertension are not well understood. Recently, genetic studies of familial primary pulmonary hypertension (FPPH) elucidated alterations in the bone morphogenetic protein receptor II (BMPRII) gene, a member of the transforming growth factor (TGF) super-family. However, although about 50% of patients with FPPH have this gene defect, only 20% of persons carrying a mutation in this gene develop PAH, clearly implicating additional host/environment interactions involving modifier genes that influence the development of PAH. In this K08 application, the PI will leverage the unique resources provided by the NHLBI-sponsored Programs in Genomic Applications (PhysGen, HopGene and TIGR) and apply contemporary genetic/genomic approaches in an established rat model of pulmonary hypertension in order to identify novel genes which are involved in the development of PAH. Specific Aim 1 will characterize PAH responses in two inbred rat strains (Brown Norway and SS Dahl) shown by the PI to differ in their susceptibility to hypoxia. Specific Aim 2 will utilize a consomic rat panel to identify chromosome-specific regulation of the rodent pulmonary hypertensive response. These consomic rats contain a single chromosome from the "resistant" parent strain introgressed into the "sensitive" strain background in order to allow the rapid isolation of the chromosome(s) containing genes that influence the development of PAH. Specific Aim 3 will next utilize congenic rats which have been rapidly generated in order to further localize the region(s) of interest. This approach, combined with extensive gene expression profiling, will allow the PI to identify quantitative trait loci (QTL)-specific candidate genes that modify the pulmonary hypertensive response. These data obtained in rats have the potential to identify relevant candidate genes which modify the susceptibility and severity of PAH in humans, utilizing highly translational approaches that can be implemented within the overarching HopGene PGA. We speculate that the elucidation of these molecular targets will lead to novel insights into the molecular mechanisms involved in human PAH and provide the rationale for novel therapies designed to improve the prognosis of patients with this devastating disease.