Sex Hormones in Pulmonarv Arterial Hypertension

项目1：该项目的目标是开发一种新的治疗肺动脉高压的方法。 基于对雌激素代谢物活性的操纵，我们认为这是遗传性心脏病病理的核心 和特发性疾病，并可能与结缔组织疾病相关的PAH。女性性别是 是PAH最强烈和最确定的危险因素，但直到最近还没有什么可以解释女性 占优势。来源的复合雌激素(如雌二醇、雌二醇)主要通过 2位或16位的羟化反应。一些受试者主要将E2代谢成2-雌激素，而 另一些则主要代谢E2至16-雌激素。在大多数受试者中，这种变异是良性的。但是，在 BMPR2突变的背景(在大多数可遗传的PAH患者中发现)这一因素提供了强大的 疾病外显性的预测。携带BMPR2突变的女性和优先选择 在我们的初步研究中，将E2代谢成16种雌激素会发展成PAH；那些优先代谢的人 雌二醇化成2-雌激素类没有。初步数据表明，雌激素代谢的这种差异在两者中都存在。 HPAH和IPAH患者，2-雌激素：16-雌激素的低比例可促进PAH。通过以下方式治疗 2-雌激素已在一些PAH模型中获得成功。确认比率失衡是有原因的，而不是 仅仅与疾病有关，我们给Bmpr2突变小鼠注射了16种雌激素，并表明它基本上 肺血管修剪加速，肺血管阻力恶化，右肺恶化 脑室(RV)扩张，对对照组小鼠影响最小。基于文献和我们的初步研究 结果：我们认为16-雌激素干扰了雌激素受体a(Era)的正常转运，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，BMPR2在HPAH和IPAH患者中低表达)，这种变异在 雌激素代谢是有害的。在这个项目中，我们有三个目标：(1)确认在 雌激素和雌激素代谢物，经内源性和外源性雌激素暴露调整后， 对人类的多环芳烃有贡献。(2)确定雌激素代谢差异性的机制 促进肺血管疾病，重点是雌激素受体运输和能量生产 缺陷。(3)确定雌激素代谢产物促进右心室分化的机制。 功能障碍，重点是能源生产缺陷。到这个项目结束时，我们预计将有 对多环芳烃进行雌激素修饰的人体试验的框架。 相关性(请参阅说明)： 大多数新发的肺动脉高压(PAH)患者在三年内死亡，即使是最好的 可用的治疗方法。大约%的PAH患者是女性，我们最近表明，她们 患上与雌激素分解方式有关的疾病。这个项目的目标是开发一种 新的、更有效的治疗方法，针对雌激素分解方式的差异。

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.