Pulmonary arterial hypertension (PAH) affects thousands of Americans of all ages, with disproportionate disease in young women. Despite recent progress PAH takes the lives of a third of all patients within 3 years. Our preliminary studies indicate that a complicate interplay of events, including altered estrogen metabolism and insulin resistance, drive energy production defects, abnormal intracellular trafficking, and cytoskeletal defects which characterize and promote the cardiovascular dysfunction characteristic of PAH. The central theme of our program is to intervene against downstream mechanisms which we have shown to be important in PAH pathogenesis and for which translational therapies are currently available. Our hypothesis is that optimal treatment of the dysfunctional metabolic pathways which underlie PAH will improve pulmonary vascular function and consequences of the disease. Our goal is to develop highly effective therapy, which will also have benefit for pulmonary hypertension which complicates many common heart and lung diseases. In Project 1 we will validate 2-methoxyestradiol as a treatment for PAH using multiple approaches, including epidemiology and functional studies of estrogen metabolite balance on lung vascular and cardiac function. This will confirm and extend studies demonstrating that diversion of estrogen metabolism away from 2- hydoxylation and towards 16?-hydroxylation contributes to excess PAH in females. In Project 2, we will test metformin as a treatment for PAH, extending our findings of insulin resistance and metabolic syndrome in PAH, using multiple approaches including metabolic phenotyping, epidemiology, and patient interventions. In project 3, we will pursue ACE2 as a treatment for PAH, extending our previous finding that ACE2 is an effective intervention in murine BMPR2-related PAH. In combination with other studies within the Vanderbilt PAH program, we plan for each of these treatments to be ready for clinical trials during a second five year period. Each of these treatments is targeted at recently identified basic pathogenetic mechanisms of disease. This novel program builds directly on recent discoveries of PAH mechanisms to develop therapeutics targeted to interdict those biologic pathways.

Public Health Relevance

Pulmonary arterial hypertension (PAH) is elevated blood pressure in the lungs, which leads to right heart failure and death. No existing treatments are very effective. This Program Project Grant aims to develop new, more effective treatments based on interventions against the hormonal, metabolic, and signaling defects recently shown to form the molecular basis for disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL108800-02
Application #
8534245
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (M1))
Program Officer
Moore, Timothy M
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$2,661,144
Indirect Cost
$919,512
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
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Evans, Jonathan D W; Girerd, Barbara; Montani, David et al. (2016) BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Lancet Respir Med 4:129-37
Hemnes, Anna R; Zhao, Min; West, James et al. (2016) Critical Genomic Networks and Vasoreactive Variants in Idiopathic Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 194:464-75
Talati, Megha H; Brittain, Evan L; Fessel, Joshua P et al. (2016) Mechanisms of Lipid Accumulation in the Bone Morphogenetic Protein Receptor Type 2 Mutant Right Ventricle. Am J Respir Crit Care Med 194:719-28
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West, James D; Carrier, Erica J; Bloodworth, Nathaniel C et al. (2016) Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension. PLoS One 11:e0148657
Brittain, Evan L; Talati, Megha; Fessel, Joshua P et al. (2016) Fatty Acid Metabolic Defects and Right Ventricular Lipotoxicity in Human Pulmonary Arterial Hypertension. Circulation 133:1936-44
Chung, Wendy K; Austin, Eric D; Best, D Hunter et al. (2015) When to offer genetic testing for pulmonary arterial hypertension. Can J Cardiol 31:544-7
Hemnes, Anna R; Trammell, Aaron W; Archer, Stephen L et al. (2015) Peripheral blood signature of vasodilator-responsive pulmonary arterial hypertension. Circulation 131:401-9; discussion 409
Newman, John H; Brittain, Evan L; Robbins, Ivan M et al. (2015) Effect of acute arteriolar vasodilation on capacitance and resistance in pulmonary arterial hypertension. Chest 147:1080-5

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