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.

Public Health Relevance

In this new project we align experienced basic and physician scientists with the goal to understand the functions of pathways which we have shown are integral in the pathogenesis of Pulmonary Arterial Hypertension (PAH). Using our large cohort of patients, as well as unique cell and animal models, we will test our hypothesis that defects in caveolae represent a common mechanism underlying the molecular basis of PAH.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111259-03
Application #
8598932
Study Section
Special Emphasis Panel (ZRG1-CVRS-H (90))
Program Officer
Caler, Elisabet V
Project Start
2012-01-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
3
Fiscal Year
2014
Total Cost
$652,780
Indirect Cost
$232,433
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Zhao, Min; Austin, Eric D; Hemnes, Anna R et al. (2014) An evidence-based knowledgebase of pulmonary arterial hypertension to identify genes and pathways relevant to pathogenesis. Mol Biosyst 10:732-40
Austin, Eric D; Loyd, James E (2014) The genetics of pulmonary arterial hypertension. Circ Res 115:189-202
Hanson, Caroline A; Drake, Kimberly R; Baird, Michelle A et al. (2013) Overexpression of caveolin-1 is sufficient to phenocopy the behavior of a disease-associated mutant. Traffic 14:663-77
Brittain, Evan L; Pugh, Meredith E; Wheeler, Lisa A et al. (2013) Prostanoids but not oral therapies improve right ventricular function in pulmonary arterial hypertension. JACC Heart Fail 1:300-7
Ma, Lijiang; Roman-Campos, Danilo; Austin, Eric D et al. (2013) A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 369:351-61