The overall purpose of this project is to determine on a molecular level how suppression or mutation of BMPR2 results in pulmonary arterial hypertension (PAH), in order to identify points for intervention. This has been a tremendous success in the first three years, as described in the progress report following. The current renewal focuses on developing our findings on a shift in energy metabolism towards glutaminolysis. Glutamine is a nonessential amino acid which in some cancers, and in PAH according to our data, has become the primary mitochondrial substrate. This increased glutamine uptake is required for cell survival and growth in BMPR2 mutants and cancer, but not in healthy tissue, making it an excellent diagnostic and therapeutic target. We first identified th shift to glutaminolysis in gene expression studies of BMPR2 mutant mice. The increased reliance on glutamine in Bmpr2 mutant cells was confirmed independently through glutamine uptake studies, stable isotope tracer studies using labeled glutamine, and through growth curves demonstrating a requirement for excess glutamine. Clinical studies demonstrated a twofold increase in serum glutamine levels in PAH patients of any etiology, combined with a 50% drop in glutamine levels across the lungs in PAH patients. This shift to reliance on glutamine has previously only been seen in neoplastic processes. The oxidative stress and metabolic defects are likely to be the basis of disease, not bystanders. We have shown in three molecularly different mouse models that these metabolic changes are part of pathogenesis, and there are now case reports on two patients in whom reversal of these changes resulted in dramatic hemodynamic improvement. The proposed studies will determine how the shift to glutaminolysis is happening, whether interfering with it is likely to be clinically useful, and whether it can be used as a diagnostic tool in patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095797-09
Application #
9392934
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Xiao, Lei
Project Start
2009-03-31
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
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