Estrogen signaling in portopulmonary hypertension

门脉性肺动脉高压中的雌激素信号传导

基本信息

批准号：
8656425
负责人：
Michael Todd Fallon
金额：
$ 70.47万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2012-05-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8656425
关键词：
2-methoxyestradiol Address Affect Age American Angiogenesis Inhibitors Animal Model Aromatase Blood Blood Vessels Bone Marrow CYP19A1 gene Cause of Death Cirrhosis Clinical Trials Cohort Studies Complication Cross-Sectional Studies Cytochrome P450 Data Development Down-Regulation ESR1 gene Enzymes Estradiol Estrogen Receptor alpha Estrogens Fulvestrant Funding General Population Genes Genetic Determinism Genetic Markers Goals Growth Hematopoietic Hypertension Incidence Individual Intervention Studies Knowledge Lead Link Liver diseases Lung Mediating Metabolism Multicenter Studies Patients Persons Population Population Control Portal Hypertension Principal Investigator Pulmonary Hypertension Rare Diseases Risk Risk Factors Signal Transduction Single Nucleotide Polymorphism Stem cells Systolic Pressure Therapy Clinical Trials Translating United States National Institutes of Health Variant Vascular Diseases Ventricular angiogenesis cohort high risk inhibitor/antagonist liver transplantation mortality novel patient oriented research progenitor programs prophylactic prospective pulmonary arterial hypertension therapeutic target treatment strategy urinary

项目摘要

Cirrhosis afflicts nearly 3 million people in the US, and complications of cirrhosis are the 4th leading cause of death in individuals ages 45-65.[1] One complication is portopulmonary hypertension (PPHTN), defined as pulmonary arterial hypertension (PAH) in the setting of portal hypertension. PPHTN is found in ~6% of patients evaluated for liver transplantation (totaling almost 170,000 Americans with PPHTN) and significantly increases mortality. There is a very poor understanding of why PAH occurs in portal hypertension and essentially no mechanistic studies of PPHTN. In fact, there has never been a large NIH-funded multicenter study of PPHTN. To address this need, the two principal investigators have executed the only NIH-funded program of patient-oriented research in PPHTN (Pulmonary Vascular Complications of Liver Disease (PVCLD) Study Group)(R03 DK064103). We showed that variation in genes linked to estrogen signaling (aromatase and estrogen receptor alpha (ESR1)) and higher estradiol levels significantly increased the risk of PPHTN in patients with advanced liver disease. However, the mechanistic link remains unknown. Animal models and patients with PAH have increased progenitor cells in the bone marrow and circulating in blood (CEPs). Estradiol stimulates CEPs via the estrogen receptor alpha (ERalpha) and alpha blockade reduces CEP colony formation. Estradiol is metabolized by cytochrome P450 1B1 (CYP1B1) to metabolites which have both pro-angiogenic (16alpha-OHE{1}) and anti-angiogenic (2-OHE, 2-methoxyestradiol (2ME)) effects. A single nucleotide polymorphism (SNP) (rs1800440) in CYP1B1 and higher urinary 16alpha-OHE1 / 2-OHE ratio are both risk factors for heritable PAH. Therefore, we hypothesize that genetic determinants increase estrogen activity and influence estradiol metabolism, leading to increased levels of CEPs (indicating greater angiogenesis) and the development of PPHTN. We propose a cross-sectional analysis of a prospective cohort and a small ¿proof-of-principle intervention study to answer three aims. We aim: 1) To determine whether variation in the rs1800440 SNP in CYP1B1 is associated with PPHTN, 2) To define the link between estrogen signaling, CEPs, and PPHTN, and 3) To determine if modulation of estrogen signaling using an ERalpha inhibitor (fulvestrant) influences CEPs and echocardiographic findings in PPHTN. The ultimate goal of this proposal is to identify mechanisms of and therapeutic targets for PPHTN. If CYP1B1 variants increase the risk of PPHTN, clinical trials using 2ME could be pursued. If we find that CEPs mediate the link between estrogen signaling and PPHTN, trials using anti-angiogenic compounds could be pursued. Finally, downregulation of CEPs by fulvestrant would identify ERalpha blockade as another approach. If these hypotheses are incorrect, we could use the genetic and biomarker data to examine alternative hypotheses.

在美国，肝硬化遭受了近300万人的困扰，肝硬化并发症是45-65岁个个人的第四大死亡原因。[1]一种并发症是门肺高血压（PPHTN），在门户高血压的情况下定义为肺动脉高压（PAH）。在评估肝移植的患者中，发现PPHTN是在约6％的患者中发现的（总计近170,000名PPHTN的美国人），并显着增加了死亡率。人们对为什么在门户高血压中发生PAH的理解非常糟糕，而基本上没有PPHTN的机械研究。实际上，从来没有进行过大型NIH资助的PPHTN多中心研究。为了满足这一需求，两名主要研究人员已经执行了唯一由NIH资助的PPHTN研究（肝病肺血管并发症（PVCLD）研究组）（R03 DK064103）的计划。我们表明，与雌激素信号传导（芳香化酶和雌激素受体α（ESR1））和较高雌二醇水平相关的基因变异显着增加了晚期肝病患者PPHTN的风险。但是，机械链接仍然未知。动物模型和PAH患者的骨髓中的祖细胞增加，血液循环（CEP）。雌二醇通过雌激素受体α（Eralpha）刺激CEP，而α封锁降低了CEP菌落的形成。雌二醇由细胞色素P450 1B1（CYP1B1）代谢，为具有亲血管生成（16alpha-Ohe {1}）和抗血管生成（2-OHE，2-甲氧基雌二醇（2me））效应的代谢产物。 CYP1B1中的单个核苷酸多态性（SNP）（SNP）（RS1800440）和较高的泌尿率16Alpha-OHE1 / 2-OHE比都是可遗传的PAH的危险因素。因此，我们假设遗传决定剂会增加雌激素活性并影响雌二醇代谢，从而导致CEP水平升高（表明更大的血管生成）和PPHTN的发展。我们提出了对前瞻性队列和小型原则干预研究的横断面分析，以回答三个目标。我们的目的：1）确定CYP1B1中RS1800440 SNP的变化是否与PPHTN相关，2）定义雌激素信号传导，CEP和PPHTN之间的联系，以及3）是否使用ERALPHA抑制剂（FellVestorant）和Ceps copsographing copsographing copsographing copsographing copsographing copsographing copsographing copsographing copsographing copsication and cocardinging sighopicagraphipplating pphttn。该提案的最终目标是确定PPHTN的机制和治疗靶标。如果CYP1B1变体增加了PPHTN的风险，则可以进行使用2ME的临床试验。如果我们发现CEPS介导雌激素信号传导与PPHTN之间的联系，则可以进行使用抗血管生成化合物的试验。最后，通过完全对CEP的下调将确定Eralpha封锁是另一种方法。这些假设是不正确的，我们可以使用遗传和生物标志物数据来检查替代假设。