Sex Hormones in Pulmonary Arterial Hypertension

肺动脉高压中的性激素

• 批准号: 10250453
• 负责人: JAMES E LOYD
• 金额: $ 62.68万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250453
• 关键词: Activities of Daily Living; Affinity; Age; Animals; Associate Degree; Biological Models; Blood; Blood Vessels; Breast; Cardiac Catheterization Procedures; Characteristics; Clinical; Consumption; Data; Defect; Diagnosis; Disease; Drops; Estradiol; Estrogen Antagonists; Estrogen Receptors; Estrogens; FDA approved; Female; Foundations; Future; Goals; Gonadal Steroid Hormones; Hormonal; Human; Hydroxyestrones; Insulin Resistance; Intervention; Isoprostanes; Lead; Lung; Measures; Mediating; Metabolic; Mitochondria; Modeling; Molecular; Oxidative Stress; PPAR gamma; Patients; Penetrance; Pharmaceutical Preparations; Pharmacology; Phenotype; Placebos; Population; Positron-Emission Tomography; Premenopause; Program Research Project Grants; Publishing; Pulmonary Hypertension; Pulmonary artery structure; Receptor Signaling; Regulation; Research Design; Right Ventricular Function; Risk Factors; Safety; Selective Estrogen Receptor Modulators; Severity of illness; Signal Transduction; Suggestion; Tamoxifen; Testing; Therapeutic; Time; Tissues; Toxic effect; Tracer; Transgenic Mice; Transgenic Model; Transgenic Organisms; Urine; Woman; anastrozole; capillary bed; cohort; curative treatments; density; estrogenic; hemodynamics; hormone therapy; improved functioning; male; malignant breast neoplasm; mitochondrial dysfunction; mouse model; novel therapeutic intervention; oxidant stress; oxidative damage; precision medicine; pressure; prevent; primary endpoint; pulmonary arterial hypertension; response; secondary endpoint; sex; therapeutically effective; treatment response; trial comparing; uptake; vascular bed; young woman

Project Summary The strongest established risk factor for the progressively fatal disease pulmonary arterial hypertension (PAH) is female sex (~3:1 ratio of females: males). Elevated circulating estrogen levels, and enhanced estrogen signaling, are a feature of PAH. Our evidence suggests that exuberant estrogen signaling causes a perturbation of mitochondrial function and energy substrate utilization in both sexes. However, not all PAH patients have elevated estrogens, and we don’t know the affinity of the pulmonary vascular bed for estrogens. In preliminary studies of PAH patients, estradiol (E2) levels were higher pre- than post-pulmonary capillary bed, suggestive of E2 uptake by the lungs. While this transpulmonary (TP) gradient was variable among patients, those with a more negative TP gradient had more severe hemodynamic metrics at diagnosis. E2 and other estrogens, such as 16α-hydroxyestrone (16αOHE1), signal via the canonical estrogen receptors (ESRα and ESRβ). In a transgenic mouse model of PAH, we found that administration of 16αOHE1 significantly increased PAH penetrance concomitant with features of oxidant stress, insulin resistance and mitochondrial dysfunction—all characteristics we and others have described in humans. ESR signaling also reduced PPARγ expression via a reduction in PGC1α. With tamoxifen, a direct ESR antagonist, we prevented the cellular metabolic defects and pulmonary vascular phenotype in our transgenic murine model system. Tamoxifen is a well-tolerated FDA-approved drug and the most commonly used hormonal therapy to antagonize ESRs. In our model system, we measured the degree of ESR antagonism by tamoxifen using a PET scan with estrogen tracer. In humans, we have applied this approach to those treated with tamoxifen for breast cancer—providing an opportunity to associate the degree of antagonism with therapeutic response. Our central hypothesis is that estrogen antagonism by tamoxifen will be a safe therapeutic approach for PAH, and that characteristics of a highly estrogenic profile in the blood and lungs will identify PAH patients likely to have the most benefit. We will test this hypothesis with these Specific Aims: (1) Test the hypothesis that estrogen antagonism with tamoxifen is safe in humans with PAH, using a 24 week proof-of-concept safety trial comparing tamoxifen (n=12) to placebo (n=12). (2) Determine the phenotype profile of subjects with PAH for whom estrogen antagonism may be an effective therapeutic approach—TP E2 levels and lung ESR density will be determined at diagnosis, and associated with disease severity. (3) Test the hypothesis that estrogen signaling drives mitochondrial fragmentation and oxidative damage leading to pulmonary hypertension via regulation of PGC1α, to uncover novel therapeutic approaches that target only the deleterious effects of estrogens in PAH. Ultimately, we aim to demonstrate the safety of direct ESR antagonism, those patients most likely to benefit, and the cellular mechanisms that drive estrogen signaling to promote PAH. This proposal should provide the foundation for a definitive trial of estrogen antagonism using a precision medicine approach.

项目摘要 进行性致死性疾病肺动脉高压（PAH）的最强风险因素 是女性性别（女性：男性比例约为3：1）。循环雌激素水平升高， 信号传导是PAH的特征。我们的证据表明，旺盛的雌激素信号传导导致 线粒体功能和能量底物利用的扰动。然而，并非所有PAH 患者雌激素水平升高，我们不知道肺血管床对雌激素的亲和力。 在PAH患者的初步研究中，雌二醇（E2）水平在肺毛细血管前高于肺毛细血管后。 床，提示肺部吸收E2。虽然这种穿透（TP）梯度是可变的， 在20例患者中，TP梯度更负的患者在诊断时具有更严重的血流动力学指标。 E2和其他雌激素，如16α-羟基雌酮（16α OHE 1），通过典型的雌激素受体发出信号 (ESRα和ESRβ）。在PAH转基因小鼠模型中，我们发现给予16α OHE 1 PAH代谢率显著增加，伴有氧化应激、胰岛素抵抗和 线粒体功能障碍-我们和其他人已经描述了人类的所有特征。ESR信号也 通过减少PGC 1 α降低了PPARγ的表达。使用他莫昔芬（一种直接的ESR拮抗剂）， 细胞代谢缺陷和肺血管表型在我们的转基因小鼠模型系统。 他莫昔芬是一种耐受性良好的FDA批准的药物，也是最常用的激素治疗， 拮抗ESRs。在我们的模型系统中，我们使用一种新的方法测量了他莫昔芬对ESR的拮抗程度。 用雌激素示踪剂做PET扫描在人类中，我们已经将这种方法应用于那些接受他莫昔芬治疗的患者， 乳腺癌-提供了将拮抗程度与治疗反应相关联的机会。 我们的中心假设是他莫昔芬的雌激素拮抗作用将是PAH的安全治疗方法， 血液和肺中高雌激素水平的特征将识别PAH患者， 有最大的好处。我们将通过以下具体目标来检验这一假设：（1）检验以下假设： 一项为期24周的概念验证安全性试验显示，他莫昔芬的雌激素拮抗作用在PAH患者中是安全的 比较他莫昔芬（n=12）与安慰剂（n=12）。(2)确定PAH受试者的表型特征， 雌激素拮抗剂可能是有效的治疗方法，TP E2水平和肺ESR密度将 在诊断时确定，并与疾病严重程度相关。(3)验证雌激素 信号传导驱动线粒体断裂和氧化损伤， PGC 1 α的调节，以发现仅针对PGC 1 α的有害作用的新治疗方法。 PAH中的雌激素。最终，我们的目标是证明直接ESR拮抗剂的安全性，这些患者最 可能受益，以及驱动雌激素信号传导促进PAH的细胞机制。这项建议 应该为使用精确医学方法进行雌激素拮抗作用的确定性试验提供基础。