Interventions Against the Molecular Etiology of BMPR2-induced PAH

针对 BMPR2 诱导的 PAH 分子病因学的干预措施

• 批准号: 8816841
• 负责人: JAMES D WEST
• 金额: $ 54.4万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816841
• 关键词: Acetylation; Avidity; BMPR2 gene; Case Study; Cell Culture Techniques; Cell Survival; Cells; Citric Acid Cycle; Clinical; Clinical Research; Data; Defect; Dependence; Development; Diagnostic; Diet; Disease; Drops; Energy Metabolism; Enzymes; Etiology; Fatty acid glycerol esters; Gene Expression; Glucose; Glutamates; Glutamine; Growth; Hour; Human; Intervention; Isocitrate Dehydrogenase; Knockout Mice; Label; Link; Lung; Lysine; Malignant Neoplasms; Measures; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Mus; Mutant Strains Mice; Mutation; Neoplastic Processes; Non-Essential Amino Acid; Organ; Oxidative Stress; Oxygen; Pathogenesis; Patients; Penetrance; Positron-Emission Tomography; Process; Progress Reports; Protein Acetylation; Pulmonary Hypertension; Pulmonary Vascular Resistance; Regulation; Serum; Sirtuins; Source; Testing; Tissues; Tracer; base; cell growth; fatty acid oxidation; hemodynamics; metabolomics; mouse model; mutant; overexpression; prevent; public health relevance; pulmonary arterial hypertension; stable isotope; success; therapeutic target; tool; treatment response; uptake

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：本项目的总体目的是在分子水平上确定BMPR 2的抑制或突变如何导致肺动脉高压（PAH），以确定干预点。正如以下进度报告所述，这在头三年取得了巨大成功。目前的更新重点是发展我们的发现，在能量代谢向β-内酰胺分解的转变。谷氨酰胺是一种非必需氨基酸，根据我们的数据，在某些癌症和PAH中，它已成为主要的线粒体底物。这种增加的谷氨酰胺摄取是BMPR 2突变体和癌症中细胞存活和生长所必需的，但在健康组织中则不然，这使其成为一种极好的诊断和治疗靶点。我们首先在BMPR 2突变小鼠的基因表达研究中发现了这种转变。通过谷氨酰胺摄取研究、使用标记的谷氨酰胺的稳定同位素示踪剂研究以及通过证明需要过量谷氨酰胺的生长曲线，独立证实了Bmpr 2突变细胞对谷氨酰胺的依赖性增加。临床研究表明，任何病因的PAH患者的血清谷氨酰胺水平增加两倍，PAH患者的整个肺部谷氨酰胺水平下降50%。这种依赖谷氨酰胺的转变以前仅见于肿瘤过程。氧化应激和代谢缺陷可能是疾病的基础，而不是旁观者。我们已经在三种分子上不同的小鼠模型中表明，这些代谢变化是发病机制的一部分，现在有两名患者的病例报告，这些变化的逆转导致了血液动力学的显著改善。拟议中的研究将确定如何转变为去甲氨醇溶解，干扰它是否可能在临床上有用，以及它是否可以用作患者的诊断工具。