PROJECT 1: The goal of this project is to develop a new therapy for pulmonary arterial hypertension (PAH) based on manipulating estrogen metabolite activity, which we believe is central to the pathology of heritable and idiopathic disease, and perhaps to PAH associated with connective tissue diseases. Female gender is the strongest and best established risk factor for PAH, but until recently there was little to explain the female predominance. Source compound estrogens (e.g., estradiol, E2) are predominantly metabolized through hydroxylation at the 2- or 16- position. Some subjects predominantly metabolize E2 to 2-estrogens, while others predominantly metabolize E2 to 16-estrogens. In most subjects, this variation is benign. However, in the context of a BMPR2 mutation (found In most heritable PAH patients) this factor provides robust prediction of disease penetrance. Women who have a BMPR2 mutation and who also preferentially metabolize E2 Into 16-estrogens develop PAH in our preliminary studies;those who preferentially metabolize E2 into 2-estrogens do not. Preliminary data suggest this difference in estrogen metabolism occurs in both HPAH and IPAH patients, and that a low ratio of 2-estrogens: 16-estrogens promotes PAH. Treatment with 2-estrogens has been successful in some PAH models. To confirm that a ratio Imbalance is causative, not just associated with disease, we gave 16-estrogens to Bmpr2 mutant mice and showed that it substantially accelerated pulmonary vascular pruning, worsened pulmonary vascular resistance, and worsened right ventricle (RV) dilation, with minimal effects In control mice. Based on the literature and our preliminary results, we believe that 16-estrogens disrupt normal trafficking of estrogen receptor a (ERa) and cause energy derangements likely attributable to tricarboxylic acid cycle (citric acid cycle) defects. In the genetically-susceptible host (e.g., BMPR2 expression Is low in HPAH and IPAH patients), this variation in estrogen metabolism is detrimental. In this project, we have three aims: (1) Confirm that variations in estrogens and estrogen metabolites, adjusted for endogenous and exogenous estrogen exposures, contribute to human PAH. (2) Determine the mechanism by which estrogen metabolites differentially promote pulmonary vascular disease with a focus on estrogen receptor trafficking and energy production defects. (3) Determine the mechanism by which estrogen metabolites differentially promote right ventricular dysfunction with a focus on energy production defects. By the conclusion of this project, we expect to have the framework on which to conduct a human trial of estrogen modification for PAH.

Public Health Relevance

Most new pulmonary arterial hypertension (PAH) patients still die within three years, even with the best available therapies. Approximately % of PAH patients are women, and we have recently shown that they develop disease linked to the way that they break down estrogens. This goal of this project is to develop a new and more effective therapy targeted at differences in how estrogen is broken down

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL108800-03
Application #
8692003
Study Section
Special Emphasis Panel (ZHL1-CSR-Q)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
$748,990
Indirect Cost
$268,868
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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