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 #
5P01HL108800-03
Application #
8692002
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (M1))
Program Officer
Xiao, Lei
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
$2,632,685
Indirect Cost
$888,626
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
Gaskill, Christa F; Carrier, Erica J; Kropski, Jonathan A et al. (2017) Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction. J Clin Invest 127:2262-2276
Chen, Xinping; Austin, Eric D; Talati, Megha et al. (2017) Oestrogen inhibition reverses pulmonary arterial hypertension and associated metabolic defects. Eur Respir J 50:
Yu, Chang; Zelterman, Daniel (2017) A parametric model to estimate the proportion from true null using a distribution for p-values. Comput Stat Data Anal 114:105-118
Austin, Eric D; Feinstein, Jeffrey A (2017) Accelerometry: Improving Objective Assessments of Therapeutic Impact in Pediatric Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 196:127-129
Austin, Eric D; West, James; Loyd, James E et al. (2017) Translational Advances in the Field of Pulmonary Hypertension Molecular Medicine of Pulmonary Arterial Hypertension. From Population Genetics to Precision Medicine and Gene Editing. Am J Respir Crit Care Med 195:23-31
Mar, Philip L; Nwazue, Victor; Black, Bonnie K et al. (2016) Valsalva Maneuver in Pulmonary Arterial Hypertension: Susceptibility to Syncope and Autonomic Dysfunction. Chest 149:1252-60
Chen, Xinping; Talati, Megha; Fessel, Joshua P et al. (2016) Estrogen Metabolite 16?-Hydroxyestrone Exacerbates Bone Morphogenetic Protein Receptor Type II-Associated Pulmonary Arterial Hypertension Through MicroRNA-29-Mediated Modulation of Cellular Metabolism. Circulation 133:82-97
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
Hay, Bryan R; Pugh, Meredith E; Robbins, Ivan M et al. (2016) Parenteral Prostanoid Use at a Tertiary Referral Center: A Retrospective Cohort Study. Chest 149:660-6
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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