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.
Substantial metabolic abnormalities are associated with the development of both idiopathic and heritable Pulmonary Arterial Hypertension (PAH). Preliminary data suggests that these abnormalities are causal for disease, via a shift to glutamine dependence otherwise only found in cancers. The proposed studies will determine how the shift to glutaminolysis is happening, whether interfering with it is likely to be clinicall useful, and whether it can be used as a diagnostic tool in patients.
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