Caveolar Defects Underlie the Genetic Origins of PAH

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DESCRIPTION (provided by applicant): Pulmonary Arterial Hypertension (PAH) is a lethal disease of all ages. It affects women disproportionately and current therapy has marginal impact on longterm survival, perhaps because it neglects pathogenesis. We have focused considerable effort in understanding the central genetic mechanisms and pathways that contribute to PAH pathogenesis, beginning with our discovery of the association of BMPR2 mutations as the major gene associated with PAH. Along with our large cohort of families with PAH (FPAH), most of whom have mutation in bone morphogenetic protein receptor 2 (BMPR2) [60 families], we constructed a Bmpr2 mutation mouse model (R899X) which recapitulates PAH. Through examination of presymptomatic BMPR2 mutant PAH patients and our mouse model, we have been able to identify several major molecular events which precede development of disease. Notable among these is disruption of trafficking of caveolae. However, which of these events are central to disease development and which are bystanders has not yet been determined. Further, the molecular basis for BMPR2-independent forms of PAH has yet to be elucidated. To address this issue, we undertook a whole-exome sequencing approach to study PAH patients without previous genetic etiology for PAH. This analysis identified a novel gene associated with human PAH, caveolin-1 (CAV1), a membrane protein important for the formation of caveolae. Importantly, caveolae are abundant in plasma membrane of multiple cell types in the lung, and have been linked to multiple signaling pathways, including BMPR2, while Cav1 null mice have no caveolae and exhibit pulmonary vascular dysfunction. Based on this convergence of CAV1 and BMPR2 mutations, we developed our hypothesis that defects in caveolae represent a common mechanism underlying the genetic basis of PAH. To test this hypothesis, we have aligned experienced basic scientists and physician scientists, and propose to carry out studies in cells, mouse models, and human patients. In Aim 1 we will test the hypothesis, in cells in vitro, that caveolin-1 and BMPR2 mutations disrupt caveolae trafficking, subsequently dysregulating caveolae-dependent signaling pathways at the cellular level. In Aim 2 we will test the hypothesis, in mice, that caveolae-dependent defects in nitration, tone, and trafficking are central to the development of PAH. Finally, in Aim 3 we will test the hypothesis that human subjects with germline mutations in CAV1 or BMPR2 have defects in caveolar structure and endothelial function, which associate with PAH penetrance and severity. These investigations will provide new basic understanding about cell and molecular pathogenesis of pathways central to PAH, and will provide promise for the future translational development of effective therapy for PAH, which is greatly needed for this tragic disease.