Sex Hormones in Pulmonarv Arterial Hypertension

肺动脉高压中的性激素

• 批准号: 8401039
• 负责人: JAMES E LOYD
• 金额: $ 72.82万
• 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/8401039
• 关键词: 2-methoxyestradiol; Affect; Animals; BMPR2 gene; Benign; Biological Markers; Blood Vessels; Breast; CYP1B1 gene; Cancer Patient; Cardiopulmonary; Cell Culture Techniques; Cell Nucleus; Cell Proliferation; Cessation of life; Chronic; Citric Acid Cycle; Clinical; Clinical Course of Disease; Clinical Trials; Connective Tissue Diseases; Cytochrome P450; Data; Defect; Development; Disease; Disease Progression; Doctor of Medicine; Endothelin Receptor Antagonist; Enzymes; Epidemiology; Estradiol; Estrogen Metabolism; Estrogen Receptors; Estrogens; Estrone; Etiology; Exposure to; Female; Gender; Gene Expression; Genetic; Genetic Polymorphism; Goals; Gonadal Steroid Hormones; Heart failure; Hormonal; Hormones; Human; Hydroxylation; Hypertension; Hypoxia; Instruction; Link; Literature; Lung; Malignant Neoplasms; Measures; Metabolic; Metabolism; Modeling; Modification; Molecular; Monocrotaline; Mus; Mutant Strains Mice; Mutation; Neoplasms; Organ; Pathology; Pathway interactions; Patients; Penetrance; Pharmaceutical Preparations; Phase II Clinical Trials; Positioning Attribute; Predisposition; Principal Investigator; Process; Production; Prostaglandins I; Publishing; Pulmonary Hypertension; Pulmonary Vascular Resistance; Right Ventricular Dysfunction; Right ventricular structure; Risk; Risk Factors; Rodent; Rodent Model; Role; Signal Transduction; Source; Specificity; Stress; Testing; Therapeutic; Time; United States; Urine; Variant; Vascular Diseases; Ventricular; Woman; analog; base; cell growth; effective therapy; epidemiologic data; human subject; hypertension control; inhibitor/antagonist; mRNA Expression; male; men; mutant; mutation carrier; neoplastic; overexpression; phosphodiesterase V; prevent; programs; promoter; pulmonary arterial hypertension; receptor; response; serotonin transporter; therapeutic development; trafficking; vasoconstriction

PROJECT 1: The goal of this project is to develop a new therapy for pulmonary arterial hypertension (PAH) based on manipulating estrogen metabolite activity, which we believe is central to the pathology of heritable and idiopathic disease, and perhaps to PAH associated with connective tissue diseases. Female gender is the strongest and best established risk factor for PAH, but until recently there was little to explain the female predominance. Source compound estrogens (e.g., estradiol, E2) are predominantly metabolized through hydroxylation at the 2- or 16- position. Some subjects predominantly metabolize E2 to 2-estrogens, while others predominantly metabolize E2 to 16-estrogens. In most subjects, this variation is benign. However, in the context of a BMPR2 mutation (found In most heritable PAH patients) this factor provides robust prediction of disease penetrance. Women who have a BMPR2 mutation and who also preferentially metabolize E2 Into 16-estrogens develop PAH in our preliminary studies; those who preferentially metabolize E2 into 2-estrogens do not. Preliminary data suggest this difference in estrogen metabolism occurs in both HPAH and IPAH patients, and that a low ratio of 2-estrogens: 16-estrogens promotes PAH. Treatment with 2-estrogens has been successful in some PAH models. To confirm that a ratio Imbalance is causative, not just associated with disease, we gave 16-estrogens to Bmpr2 mutant mice and showed that it substantially accelerated pulmonary vascular pruning, worsened pulmonary vascular resistance, and worsened right ventricle (RV) dilation, with minimal effects In control mice. Based on the literature and our preliminary results, we believe that 16-estrogens disrupt normal trafficking of estrogen receptor a (ERa) and cause energy derangements likely attributable to tricarboxylic acid cycle (citric acid cycle) defects. In the genetically-susceptible host (e.g., BMPR2 expression Is low in HPAH and IPAH patients), this variation in estrogen metabolism is detrimental. In this project, we have three aims: (1) Confirm that variafions in estrogens and estrogen metabolites, adjusted for endogenous and exogenous estrogen exposures, contribute to human PAH. (2) Determine the mechanism by which estrogen metabolites differentially promote pulmonary vascular disease with a focus on estrogen receptor trafficking and energy production defects. (3) Determine the mechanism by which estrogen metabolites differentially promote right ventricular dysfunction with a focus on energy production defects. By the conclusion of this project, we expect to have the framework on which to conduct a human trial of estrogen modification for PAH. RELEVANCE (See instructions): Most new pulmonary arterial hypertension (PAH) pafients sfill die within three years, even with the best available therapies. Approximately % of PAH patients are women, and we have recently shown that they develop disease linked to the way that they break down estrogens. This goal of this project is to develop a new and more effective therapy targeted at differences in how estrogen is broken down.

项目 1：该项目的目标是开发一种治疗肺动脉高压 (PAH) 的新疗法 基于操纵雌激素代谢活性，我们认为这是遗传性病理学的核心 和特发性疾病，或许还与结缔组织疾病相关的多环芳烃有关。女性性别是 是 PAH 最强且最明确的危险因素，但直到最近还没有什么可以解释女性 优势。源化合物雌激素（例如雌二醇、E2）主要通过 2-位或16-位羟基化。一些受试者主要将 E2 代谢为 2-雌激素，而 其他人主要将 E2 代谢为 16-雌激素。在大多数受试者中，这种变异是良性的。然而，在 BMPR2 突变（在大多数遗传性 PAH 患者中发现）的背景下，该因素提供了强有力的 疾病外显率的预测。具有 BMPR2 突变且也优先考虑的女性 在我们的初步研究中，将 E2 代谢为 16-雌激素会导致 PAH；优先代谢的人 E2不转化为2-雌激素。初步数据表明雌激素代谢的这种差异发生在 HPAH 和 IPAH 患者，以及 2-雌激素：16-雌激素的低比例会促进 PAH。治疗用 2-雌激素在一些 PAH 模型中取得了成功。确认比率不平衡是原因，而不是 仅仅与疾病相关，我们给 Bmpr2 突变小鼠注射 16-雌激素，结果表明它显着 肺血管修剪加速，肺血管阻力恶化，右肺血管恶化 心室（RV）扩张，对对照小鼠的影响最小。根据文献和我们的初步 结果，我们认为 16-雌激素会破坏雌激素受体 a (ERa) 的正常运输并导致 能量紊乱可能归因于三羧酸循环（柠檬酸循环）缺陷。在 遗传易感宿主（例如，HPAH 和 IPAH 患者中 BMPR2 表达较低），这种变异 雌激素代谢是有害的。在这个项目中，我们有三个目标：（1）确认 雌激素和雌激素代谢物，根据内源性和外源性雌激素暴露进行调整， 有助于人类多环芳烃。 (2)确定雌激素差异代谢的机制 促进肺血管疾病，重点关注雌激素受体运输和能量产生 缺陷。 (3)确定雌激素代谢物差异性促进右心室的机制 功能障碍，重点是能量产生缺陷。到该项目结束时，我们预计 进行针对多环芳烃的雌激素修饰人体试验的框架。 相关性（参见说明）： 大多数新发肺动脉高压（PAH）患者在三年内就会死亡，即使是最好的肺动脉高压患者也会在三年内死亡。 可用的疗法。大约 % 的 PAH 患者是女性，我们最近的研究表明，她们 罹患疾病与它们分解雌激素的方式有关。该项目的目标是开发一个 针对雌激素分解方式差异的新的、更有效的疗法。