Hormonal, Metabolic and Signaling Interactions in PAH

PAH 中的激素、代谢和信号传导相互作用

基本信息

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
项目类别：
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

项目摘要

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.

描述：肺动脉高压（PAH）会影响所有年龄段的成千上万的美国人，年轻妇女的疾病不成比例。尽管最近进展，PAH将在3年内夺走了所有患者中三分之一的生命。我们的初步研究表明，事件的相互作用复杂，包括改变的雌激素代谢和胰岛素抵抗，驱动能量生产缺陷，异常细胞内运输以及细胞骨架缺陷，这些缺陷表征和促进了心血管血管功能障碍的特征。我们计划的中心主题是干预下游机制，我们证明，这些机制在PAH发病机理中很重要，并且目前可以使用转化疗法。我们的假设是，对PAH的基础功能失调的代谢途径的最佳治疗将改善疾病的肺血管功能和后果。我们的目标是开发高效的疗法，这也将对肺动脉高压有益，这使许多常见的心脏和肺部疾病复杂化。在项目1中，我们将使用多种方法验证2-甲氧基丙二醇作为PAH的治疗方法，包括在肺血管和心脏功能上的雌激素代谢物平衡的流行病学和功能研究。这将证实并扩展研究表明，雌激素代谢从2-羟基化转移到16？ - 羟基化会导致女性中过量的PAH。在项目2中，我们将测试二甲双胍作为对PAH的治疗方法，以使用多种方法，包括代谢表型，流行病学和患者干预措施，扩展了PAH中胰岛素抵抗和代谢综合征的发现。在项目3中，我们将追求ACE2作为PAH的治疗方法，扩展了我们先前的发现ACE2是对Myrine BMPR2相关PAH的有效干预。结合范德比尔特PAH计划中的其他研究，我们计划在第二个五年内准备每一种治疗方法进行临床试验。这些治疗中的每一个都针对最近确定的疾病的基本致病机制。这个新颖的程序直接建立在PAH机制的最新发现基础上，以开发用于阻止这些生物学途径的治疗剂。