tPPG: Vascular Sub-Phenotypes of Lung Disease
The tPPG is composed of three projects, each with a component of basic science as well as a trial of a promising new drug therapy. Project 1, led by Mark Gladwin, MD, focuses on nitrite therapy for patients with pulmonary hypertension coupled with heart failure with preserved ejection fraction. Project 2, led by Bruce Freeman, PhD, focuses on electrophilic nitro-fatty acid therapy for sufferers of pulmonary arterial hypertension. Project 3, led by Alison Morris, MD, MS, focuses on the contributions of the microbiome to the reduction of nitrate to nitrite, and the downstream products of this in vivo metabolism to nitric oxide and fatty acid nitration products.
Project 1: Exploring the Effects of Oral Nitrite Therapy on Exercise Capacity, Hemodynamics, and Insulin Resistance in Subjects with PH-HFpEF
Dr. Gladwin’s project explores the hypothesis that new vascular-targeted, nitric oxide-based therapeutic strategies will enhance the treatment of pulmonary arterial hypertension and metabolic syndrome, providing a new therapy for the currently untreatable and extremely common pulmonary hypertension in the setting of heart failure with preserved ejection fraction (PH-HFpEF). To this end, Dr. Gladwin’s team has identified two reactive nitrogen species that potently modulate both pulmonary hypertension and the metabolic syndrome, nitrite (NO2-) and nitro-fatty acids (NO2-FA).
Mark Gladwin, MD
Principal Investigator
Charlie McTiernan, PhD
Frank Sciurba, MD
Jesus Tejero, PhD
Project 2: Establishing the Safety and Efficacy of OA-NO2 Therapy in Subjects with Pulmonary Arterial Hypertension and Metabolic Syndrome
Dr. Freeman’s team hypothesizes that the promotion of nitro-fatty acid signaling alleviates metabolic syndrome-induced hypertension and its pulmonary complications. The overarching goal is to characterize and deploy a product of nitrate-nitrite-nitric oxide metabolism, electrophilic nitro-fatty acids (NO2-FA), as a new therapeutic strategy for pulmonary arterial hypertension. Researchers will unravel the roles of fatty acids in transducing nitrogen oxide signaling by studying the responses of candidate NO2-FA-regulated enzymes and key transcriptional regulatory protein targets.
Bruce Freeman, PhD
Principal Investigator
Nicholas Khoo, PhD
Patrick Pagano, PhD
Stacy Wendell, PhD
Steven Woodcock, PhD
Project 3: Exploring the Genetic, Microbiome, and Environmental Determinants of Pulmonary Hypertension
The goal of this project is to define the relationships between pulmonary hypertension, high fat diet, the oral and gut microbiome, and the metabolism of nitrogen oxide signaling mediators that may regulate the development, severity, and treatment of pulmonary hypertension. Dr. Morris’s team hypothesizes that the commensal microbiome can be beneficial in pulmonary hypertension because of its function in bioactivation of the nitrate-nitrite-nitric oxide-nitro-fatty acid pathway.
Alison Morris, MD, MS
Principal Investigator
Imad al Ghouleh, PhD
Takis Benos, PhD
Meghan Fitzpatrick, MD
Carl Koch, MD
Barbara Methé, PhD
Chris O'Donnell, PhD
Michael Risbano, MD, MA
The goals of this tPPG-funded collaboration are supported by a pre-clinical assessment core; a bioanalytical core, led by Sruti Shiva, PhD; a clinical core; and an administrative core, led by Mark Gladwin, MD.
Publications
Al Ghouleh I, Meijles DN, Mutchler S, Zhang Q, Sahoo S, Gorelova A, Henrich Amaral J, Rodriguez AI, Mamonova T, Song GJ, Bisello A, Friedman PA, Cifuentes-Pagano, ME, Pagano PJ. (2016) Binding of EBP50 to Nox organizing subunit p47phox is pivotal to cellular reactive species generation and altered vascular phenotype. Proc Natl Acad Sci USA. 113(36):E5308-17. [PMID 27540115 | PMCID PMC5018796]
Simon MA, Vanderpool RR, Nouraie M, Bachman TN, White PM, Sugahara M, Gorcsan J 3rd, Parsley EL, Gladwin MT. (2016) Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction. JCI Insight. 1(18):e89620. [PMID 27812547 | PMCID PMC5085611]
Sahoo S, Meijles DN, Al Ghouleh I, Tandon M, Cifuentes-Pagano ME, Sembrat J, Rojas M, Goncharova EA, Pagano PJ. (2016) MEF2C-MYOCD and Leiomodin1 Suppression by miRNA-214 Promotes Smooth Muscle Cell Phenotype Switching in Pulmonary Arterial Hypertension. PLoS One. 11(5):e0153780. [PMID 27144530 | PMCID PMC4856285]
Koch CD, Gladwin MT, Freeman BA, Lundberg JO, Weitzberg E, Morris A. (2016) Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health. Free Radic Biol Med. pii: S0891-5849(16)31102-9. [PMID 27989792]
Pre-Clinical Assessment Core
Claudette St. Croix, PhD
Imaging Core Director
Bioanalytic Core
Sruti Shiva, PhD
Leader
Stacy Wendell, PhD
Co-Investigator
Clinical Core
Seyed Mehdi Nouraie, MD, PhD
Statitician
Yingze Zhang, PhD
Translational Research Core Lab Director
Administrative Core
Mark Gladwin, MD
Leader
Christopher O'Donnell, PhD
Core Director
Internal Advisory Board
Timothy Billiar, MD
Flordeliza Villanueva, MD
Steven Reis, MD
External Advisory Board
Serpil Erzurum, MD, PhD
Cleveland Clinic
Stanley Hazen, MD, PhD
Cleveland Clinic
Henry Masur, MD
NIH Clinical Center