Sex Hormones in Pulmonarv Arterial Hypertension

项目1：本项目的目标是开发一种新的肺动脉高压（PAH）治疗方法 基于操纵雌激素代谢活性，我们认为这是遗传性乳腺癌病理学的核心。 和特发性疾病，以及可能与结缔组织疾病相关的PAH。女性性别是 PAH的最强和最好的确定的风险因素，但直到最近几乎没有解释女性 优势源化合物雌激素（例如，雌二醇（E2）主要通过 在2-或16-位羟基化。一些受试者主要将E2代谢为2-雌激素，而 其它的主要代谢E2为16-雌激素。在大多数受试者中，这种变化是良性的。但在 在BMPR 2突变的背景下（在大多数遗传性PAH患者中发现），该因素提供了稳健的 预测疾病复发率。有BMPR 2突变的女性， 在我们的初步研究中，将E2代谢为16-雌激素会导致PAH;那些优先代谢E2的人 E2转化为2-雌激素不。初步数据表明，雌激素代谢的这种差异发生在 HPAH和IPAH患者，低比例的2-雌激素：16-雌激素促进PAH。治疗 2-雌激素在一些PAH模型中是成功的。为了确认比率失衡是原因，而不是 我们给Bmpr 2突变小鼠16-雌激素，结果显示， 加速肺血管修剪，恶化肺血管阻力，恶化右 心室（RV）扩张，在对照小鼠中具有最小影响。根据文献和我们的初步研究， 结果，我们认为16-雌激素破坏了雌激素受体a（ER a）的正常运输， 可能归因于三羧酸循环（柠檬酸循环）缺陷的能量紊乱。在 遗传易感宿主（例如，BMPR 2在HPAH和IPAH患者中的表达较低），这种变化在 雌激素代谢是有害的。在本项目中，我们有三个目标：（1）确认 雌激素和雌激素代谢物，调整内源性和外源性雌激素暴露， 导致人类PAH。(2)确定雌激素代谢差异的机制 促进肺血管疾病，重点是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。到本项目结束时，我们预计 在此基础上进行雌激素修饰治疗PAH的人体试验。 相关性（参见说明）： 大多数新的肺动脉高压（PAH）患者在三年内死亡，即使是最好的 可用的疗法。大约%的PAH患者是女性，我们最近的研究表明， 发展出与它们分解雌激素有关的疾病。这个项目的目标是开发一个 新的和更有效的治疗针对不同的雌激素是如何分解。

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.