In this program project, we propose a Personalized Medicine approach to the study of advanced lung disease. We hypothesize that sub-phenotypes of common diseases, including pulmonary arterial hypertension (PAH), have a profound influence on outcome and responsiveness to therapy. The overarching translatlonal goal of this program is to define common mechanistic and therapeutic pathways for PAH in the context of major lung and systemic diseases, such as COPD and HIV. Our proposed three major projects and two cores are designed to integrate and synergize fundamental translatlonal research addressing major current and high impact problems in the PAH and advanced lung disease field. Because translational medicine requires a bench-to-bedside-to-bench integrated approach, we developed a full translatlonal continuum from preclinical models in three species, including a novel primate PAH model, screening and clinical drug development programs, human hemodynamic phenomic assessments, genetics, and clinical epidemiological trials focused initially on two major disease targets, COPD and HIV, which represent two prototypic models of the pulmonary hypertension sub-phenotype. Our three proposed projects and cores all individually and collaboratively align across this translational spectrum, driving an effort to understand fundamental mechanisms of disease, identify small molecule therapeutic agents, develop screening biomarkers for vascular sub-phenotypes of lung disease, and to set the stage for phase II and III clinical trials. Successes in the first five years of this project are expected to develop into phase ll-lll clinical trials and extension to other advanced lung diseases, such as interstitial lung disease and obstructive sleep apnea, in years 6 to 10. Project 1: Pulmonary hypertension in COPD: Genetic and Environmental Determinants Project 2: ROS signaling and NOS uncoupling in pulmonary vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core

Public Health Relevance

Pulmonary vascular disease is a relatively understudied, but Important sub-phenotype in COPD, HIV, IPF, and OSA that is associated with excessive morbidity and mortality, and presents unique therapeutic opportunities.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL103455-03
Application #
8469895
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M1))
Program Officer
Moore, Timothy M
Project Start
2011-06-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$2,437,938
Indirect Cost
$828,738
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kanias, Tamir; Sinchar, Derek; Osei-Hwedieh, David et al. (2016) Testosterone-dependent sex differences in red blood cell hemolysis in storage, stress, and disease. Transfusion 56:2571-2583
Procter, Nathan Ek; Ball, Jocasta; Ngo, Doan Tm et al. (2016) Gender and tachycardia: independent modulation of platelet reactivity in patients with atrial fibrillation. J Geriatr Cardiol 13:202-8
Vanderpool, Rebecca R; Rischard, Franz; Naeije, Robert et al. (2016) Simple functional imaging of the right ventricle in pulmonary hypertension: Can right ventricular ejection fraction be improved? Int J Cardiol 223:93-94
Maron, Bradley A; Gladwin, Mark T; Simon, Marc A (2016) Update in Pulmonary Vascular Disease 2015. Am J Respir Crit Care Med 193:1337-44
Gladwin, Mark T (2016) Cardiovascular complications and risk of death in sickle-cell disease. Lancet 387:2565-74
Ambrozova, Gabriela; Martiskova, Hana; Koudelka, Adolf et al. (2016) Nitro-oleic acid modulates classical and regulatory activation of macrophages and their involvement in pro-fibrotic responses. Free Radic Biol Med 90:252-60
Al Ghouleh, Imad; Meijles, Daniel N; Mutchler, Stephanie et al. (2016) Binding of EBP50 to Nox organizing subunit p47phox is pivotal to cellular reactive species generation and altered vascular phenotype. Proc Natl Acad Sci U S A 113:E5308-17
Azarov, Ivan; Wang, Ling; Rose, Jason J et al. (2016) Five-coordinate H64Q neuroglobin as a ligand-trap antidote for carbon monoxide poisoning. Sci Transl Med 8:368ra173
Meijles, Daniel N; Pagano, Patrick J (2016) Nox and Inflammation in the Vascular Adventitia. Hypertension 67:14-9
Ambrozova, Gabriela; Fidlerova, Tana; Verescakova, Hana et al. (2016) Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition. Biochim Biophys Acta 1860:2428-37

Showing the most recent 10 out of 132 publications