The PI of this K23 application is a physician-scientist with a career focus on developing improved care for patient with Pulmonary Arterial Hypertension (PAH), a rare but debilitating and fatal disease for which there is currently no available cure. Current treatment options target the cellular dysfunction that leads to constriction of the vasculature and produce pulmonary vasodilation. While these agents limit clinical deterioration and lower pulmonary pressures, their ability to produce, retard or reverse frank vascular remodeling is limited. Accumulating evidence suggests that carbon monoxide (CO) confers potent cytoprotection via anti-inflammatory, anti-proliferative and anti-apoptotic effects, processes critical for repair and remodeling of injured tissues, including those found in PAH. Specifically, exogenous delivery of inhaled CO prevents and reverses established PAH in multiple animal models. Within a highly mentored training program with staggering expertise available to the PI with the PI's mentor and Advisory Committee, the PI will explore the development and utilization of CO-based therapies that target PAH pathobiological processes. The hypotheses tested include: i) inhaled CO regulates physiologic, cellular and molecular pathways in patients with PAH which result in attenuation of pulmonary vascular remodeling;ii) a molecular signature can be defined in peripheral blood mononuclear leukocytes (PBMCs) which predict CO responsiveness. To address these hypotheses, in Specific Aim #1 the PI will conduct a phase I trial to establish safety and efficacy of inhaled CO when added to standard therapy in patients with severe PAH.
Specific Aim #2 will define a genomic signature in PBMCs as biomarkers of responsiveness to CO inhalation in patients with severe PAH.
In Specific Aim #3 we will prospectively validate the utility of the PBMC molecular signature as a biomarker of a beneficial response to CO therapy in patients with severe PAH. Together, these studies provide an outstanding curriculum for the PI to receive essential training in clinical research and develop skills in novel, highly translational approaches which will identify novel targets and biomarkers and may lead to better treatment options for patients with PAH.

Public Health Relevance

This project will investigate the use of carbon monoxide as a new treatment for pulmonary hypertension, a disease that affects the arterial blood vessels of the lungs and leads to heart failure and death. We will also investigate the role of genetic markers as a tool to identify patients with pulmonary hypertension likely to respond to carbon monoxide therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL098454-03
Application #
8269044
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2010-08-11
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$131,382
Indirect Cost
$9,732
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Saraf, Santosh L; Zhang, Xu; Kanias, Tamir et al. (2014) Haemoglobinuria is associated with chronic kidney disease and its progression in patients with sickle cell anaemia. Br J Haematol 164:729-39
Desai, Ankit A; Patel, Amit R; Ahmad, Homaa et al. (2014) Mechanistic insights and characterization of sickle cell disease-associated cardiomyopathy. Circ Cardiovasc Imaging 7:430-7
Chen, Jiwang; Tang, Haiyang; Sysol, Justin R et al. (2014) The sphingosine kinase 1/sphingosine-1-phosphate pathway in pulmonary arterial hypertension. Am J Respir Crit Care Med 190:1032-43
Zhang, Xu; Zhang, Wei; Ma, Shwu-Fan et al. (2014) Iron deficiency modifies gene expression variation induced by augmented hypoxia sensing. Blood Cells Mol Dis 52:35-45
Zhang, Xu; Zhang, Wei; Ma, Shwu-Fan et al. (2014) Hypoxic response contributes to altered gene expression and precapillary pulmonary hypertension in patients with sickle cell disease. Circulation 129:1650-8
Duarte, Julio D; Hanson, Rebekah L; Machado, Roberto F (2013) Pharmacologic treatments for pulmonary hypertension: exploring pharmacogenomics. Future Cardiol 9:335-49
Mehari, Alem; Alam, Shoaib; Tian, Xin et al. (2013) Hemodynamic predictors of mortality in adults with sickle cell disease. Am J Respir Crit Care Med 187:840-7
Machado, Roberto F; Farber, Harrison W (2013) Pulmonary hypertension associated with chronic hemolytic anemia and other blood disorders. Clin Chest Med 34:739-52
Mehari, Alem; Gladwin, Mark T; Tian, Xin et al. (2012) Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA 307:1254-6
Machado, Roberto F; Hildesheim, Mariana; Mendelsohn, Laurel et al. (2011) NT-pro brain natriuretic peptide levels and the risk of death in the cooperative study of sickle cell disease. Br J Haematol 154:512-20