Hormonal, Metabolic and Signaling Interactions in PAH

PAH 中的激素、代谢和信号传导相互作用

• 批准号: 8337996
• 负责人: JAMES E LOYD
• 金额: $ 266.73万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8337996
• 关键词: 2-methoxyestradiol; Address; Affect; Age; American; BMPR2 gene; Blood Glucose; Blood Pressure; Blood Vessels; CYP1B1 gene; Cardiac; Cardiovascular system; Categories; Cells; Cessation of life; Characteristics; Citric Acid Cycle; Clinical Research; Clinical Trials; Complication; Defect; Disease; Disease Marker; Doctor of Medicine; Employee Strikes; Energy Metabolism; Epidemiology; Equilibrium; Estrogen Metabolism; Estrogens; Event; Family; Female; Functional disorder; Funding; Future; Gene Expression; General Population; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Glucose; Goals; Heart; Heart Diseases; Heart failure; Hormonal; Hour; Human; Hydroxyestrones; Hydroxylation; Hyperglycemia; Insulin Resistance; Intervention; Isocitrate Dehydrogenase; Isoprostanes; Lipids; Lung; Lung diseases; Measurable; Measurement; Meta-Analysis; Metabolic; Metabolic Pathway; Metabolic syndrome; Metabolism; Metformin; Molecular; Mus; Mutant Strains Mice; Mutation; Nature; Oxidative Stress; Oxygen; Participant; Pathogenesis; Pathway interactions; Patients; Peptidyl-Dipeptidase A; Phenotype; Predisposition; Principal Investigator; Production; Program Research Project Grants; Proteolysis; Published Comment; Publishing; Pulmonary Hypertension; Pulmonary Vascular Resistance; Regimen; Reliance; Reporting; Sampling; Signal Transduction; Staging; Syndrome; Testing; Vascular Diseases; aerobic glycolysis; base; design; effective intervention; effective therapy; improved; in vivo; insulin sensitivity; mouse model; mutant; mutation carrier; novel; novel strategies; oxidation; oxidized lipid; preference; programs; pulmonary arterial hypertension; response; small molecule; steroid hormone receptor; therapeutic target; trafficking; young woman

DESCRIPTION: Pulmonary arterial hypertension (PAH) affects thousands of Americans of all ages, with disproportionate disease in young women. Despite recent progress PAH takes the lives of a third of all patients within 3 years. Our preliminary studies indicate that a complicate interplay of events, including altered estrogen metabolism and insulin resistance, drive energy production defects, abnormal intracellular trafficking, and cytoskeletal defects which characterize and promote the cardiovascular dysfunction characteristic of PAH. The central theme of our program is to intervene against downstream mechanisms which we have shown to be important in PAH pathogenesis and for which translational therapies are currently available. Our hypothesis is that optimal treatment of the dysfunctional metabolic pathways which underlie PAH will improve pulmonary vascular function and consequences of the disease. Our goal is to develop highly effective therapy, which will also have benefit for pulmonary hypertension which complicates many common heart and lung diseases. In Project 1 we will validate 2-methoxyestradiol as a treatment for PAH using multiple approaches, including epidemiology and functional studies of estrogen metabolite balance on lung vascular and cardiac function. This will confirm and extend studies demonstrating that diversion of estrogen metabolism away from 2- hydoxylation and towards 16?-hydroxylation contributes to excess PAH in females. In Project 2, we will test metformin as a treatment for PAH, extending our findings of insulin resistance and metabolic syndrome in PAH, using multiple approaches including metabolic phenotyping, epidemiology, and patient interventions. In project 3, we will pursue ACE2 as a treatment for PAH, extending our previous finding that ACE2 is an effective intervention in murine BMPR2-related PAH. In combination with other studies within the Vanderbilt PAH program, we plan for each of these treatments to be ready for clinical trials during a second five year period. Each of these treatments is targeted at recently identified basic pathogenetic mechanisms of disease. This novel program builds directly on recent discoveries of PAH mechanisms to develop therapeutics targeted to interdict those biologic pathways.

肺动脉高压（PAH）影响了成千上万的各个年龄段的美国人，在年轻女性中发病率不成比例。尽管最近取得了进展，但多环芳烃在3年内夺走了三分之一患者的生命。我们的初步研究表明，包括雌激素代谢改变和胰岛素抵抗在内的复杂事件相互作用，驱动能量产生缺陷，细胞内异常运输和细胞骨架缺陷，这些缺陷表征并促进了PAH的心血管功能障碍特征。我们项目的中心主题是干预下游机制，我们已经证明下游机制在多环芳烃发病机制中很重要，目前可用于转化治疗。我们的假设是，对造成多环芳烃的功能失调代谢途径进行最佳治疗，将改善肺血管功能和疾病后果。我们的目标是开发高效的治疗方法，这也将有利于肺动脉高压并发症的许多常见的心脏和肺部疾病。在项目1中，我们将使用多种方法验证2-甲氧基雌二醇作为PAH的治疗方法，包括流行病学和雌激素代谢物平衡对肺血管和心脏功能的功能研究。这将证实并扩展雌激素代谢从2-羟基化转向16？-羟基化导致女性体内多环芳烃过量。在项目2中，我们将测试二甲双胍作为PAH的治疗方法，使用多种方法，包括代谢表型，流行病学和患者干预，扩展我们在PAH中胰岛素抵抗和代谢综合征的发现。在项目3中，我们将继续研究ACE2作为PAH的治疗方法，扩展我们之前的发现，即ACE2可以有效干预小鼠bmpr2相关的PAH。结合范德比尔特多环芳烃项目的其他研究，我们计划在第二个五年期间为每一种治疗方法做好临床试验的准备。这些治疗方法中的每一种都针对最近确定的疾病的基本发病机制。这个新项目直接建立在最近发现的多环芳烃机制的基础上，以开发靶向阻断这些生物途径的治疗方法。