Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease that leads to deterioration in cardiopulmonary function and premature death. Metabolic dysregulation has emerged as a major area of research in the pathobiology of IPAH, including the altered bioavailability of nitric oxide (NO) and dysregulated glucose metabolism. Several processes may be governed by the metabolic dysfunction present in IPAH, including enhanced pulmonary vascular cell proliferation and vasoconstriction. Our long-term goal is to understand the role of the metabolic abnormalities in IPAH pathogenesis in order to design therapeutic interventions for the disease. Our effectiveness to design therapies in IPAH will be enhanced by understanding the link between glucose dysregulation, aberrant cell proliferation, and NO deficiency in the human disease and experimental animal models. The central hypothesis of this proposal is that abnormal glucose utilization and flux through the hexosamine biosynthetic pathway (HBP) drives cell proliferation and NO deficiency in IPAH. The hypothesis has been formulated based on our already published studies and recently generated preliminary data in humans and animal models. Our rationale for the proposed research is designed to establish the effects of glucose key metabolic dysregulation in IPAH by focusing on the rate-limiting OGT/O- GlcNAc axis of the HBP. Mechanistic insights will be gained by studying the HBP in animal models of the disease. The potential of this axis as a therapeutic target in IPAH will be tested by evaluating whether the OGT/O-GlcNAc axis and disease outcomes are modifiable by diet and exercise. Thus, we will test this hypothesis by pursuing the following specific aims:
AIM 1) Determine the mechanistic role of the OGT/O- GlcNAc axis in cell proliferation in IPAH and experimental animal models of the disease;
AIM 2) Investigate the specific molecular regulation of eNOS activity by O-GlcNAc in IPAH pathogenesis;
and AIM 3) Establish glucose metabolic dysregulation as a modifiable marker of clinical outcomes in IPAH. The proposed research is significant because it will: (i) establish glucose dysregulation, through the HBP and the OGT/O-GlcNAc axis as the driver for the abnormal pulmonary vascular cell proliferation; (ii) determine the extent to which these metabolic abnormalities correlate with IPAH severity and outcomes, and (iii) establish an exercise and diet intervention as a means of improving disease outcomes.

Public Health Relevance

The proposed research is relevant to public health because, to date, cures for pulmonary hypertension are not available. Pulmonary hypertension is a progressive disease that leads to deterioration in lung and heart health and premature death. We have new information suggesting that subtle changes in how the body handles glucose may cause or worsen the disease. In this proposal, we will study this concept and determine whether exercise and diet programs can improve disease outcomes. Our proposed work is relevant to the NHLBI's mission to promote the prevention and treatment of cardiopulmonary diseases and enhance human life and well-being.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Fessel, Joshua P
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Barnes, Jarrod W; Dweik, Raed A (2017) Pulmonary Hypertension and Precision Medicine through the ""Omics"" Looking Glass. Am J Respir Crit Care Med 195:1558-1560
Heresi, Gustavo A; Malin, Steven K; Barnes, Jarrod W et al. (2017) Abnormal Glucose Metabolism and High-Energy Expenditure in Idiopathic Pulmonary Arterial Hypertension. Ann Am Thorac Soc 14:190-199