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
Meoli, David F; Su, Yan Ru; Brittain, Evan L et al. (2018) The transpulmonary ratio of endothelin 1 is elevated in patients with preserved left ventricular ejection fraction and combined pre- and post-capillary pulmonary hypertension. Pulm Circ 8:2045893217745019
Yan, Ling; Cogan, Joy D; Hedges, Lora K et al. (2018) The Y Chromosome Regulates BMPR2 Expression via SRY: A Possible Reason ""Why"" Fewer Males Develop Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 198:1581-1583
Whitaker, Morgan E; Nair, Vineet; Sinari, Shripad et al. (2018) Diabetes Mellitus Associates with Increased Right Ventricular Afterload and Remodeling in Pulmonary Arterial Hypertension. Am J Med 131:702.e7-702.e13
Hemnes, Anna R (2018) Using Omics to Understand and Treat Pulmonary Vascular Disease. Front Med (Lausanne) 5:157
Han, MeiLan K; Arteaga-Solis, Emilio; Blenis, John et al. (2018) Female Sex and Gender in Lung/Sleep Health and Disease. Increased Understanding of Basic Biological, Pathophysiological, and Behavioral Mechanisms Leading to Better Health for Female Patients with Lung Disease. Am J Respir Crit Care Med 198:850-858
Brittain, Evan L; Thennapan, Thennapan; Maron, Bradley A et al. (2018) Update in Pulmonary Vascular Disease 2016 and 2017. Am J Respir Crit Care Med 198:13-23
Suzuki, Toshio; Carrier, Erica J; Talati, Megha H et al. (2018) Isolation and characterization of endothelial-to-mesenchymal transition cells in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 314:L118-L126
Halliday, Stephen J; Xu, Meng; Thayer, Timothy E et al. (2018) Clinical and genetic associations with prostacyclin response in pulmonary arterial hypertension. Pulm Circ 8:2045894018800544
Hemnes, Anna R; Rathinasabapathy, Anandharajan; Austin, Eric A et al. (2018) A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension. Eur Respir J 51:
Welch, Caitlin E; Brittain, Evan L; Newman, Alexander L et al. (2017) End-Tidal Carbon Dioxide as a Prognostic Feature in Pulmonary Arterial Hypertension. Ann Am Thorac Soc 14:896-902

Showing the most recent 10 out of 56 publications