Variations in estrogen exposures may modify pulmonary arterial hypertension

雌激素暴露的变化可能会改变肺动脉高压

基本信息

批准号：
8669054
负责人：
Eric Douglas Austin
金额：
$ 13.04万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8669054
关键词：
Adult Affect Age Androgens BMPR2 gene CYP19A1 gene CYP1A1 gene CYP1B1 gene CYP3A4 gene Candidate Disease Gene Cell Line Clinical Clinical Trials Collaborations Cytochrome P450 DNA Library Data Development Diagnosis Discipline Disease ESR1 gene ESR2 gene Endocrinology Endogenous Factors Endothelial Cells Environment Environmental Risk Factor Enzymes Epidemiologic Studies Estrogen Antagonists Estrogen Metabolism Estrogens Extramural Activities Female Fibroblasts Funding Future Gender Gene Expression Genes Genetic Genetic Polymorphism Genotype Goals Gonadal Steroid Hormones HSD17B2 gene Health High Prevalence Histopathology Hydroxyestrones In Vitro Inherited Investigation Laboratories Lung Lung diseases Mass Spectrum Analysis Master of Science Master&apos s Degree Mediating Mediator of activation protein Mentors Mentorship Metabolism Mutation National Heart, Lung, and Blood Institute Odds Ratio Pathogenesis Patients Pediatrics Pharmacologic Substance Physicians Pregnancy Prevalence Pulmonary Hypertension Reporting Research Research Training Risk Risk Factors SHBG gene Scientist Testing Testosterone Training United States National Institutes of Health Universities Variant Woman bone morphogenic protein career career development case control cohort design estrogenic activity experience genetic epidemiology genetic risk factor high risk hormone metabolism male member men mutation carrier patient oriented research prepuberty professor programs pulmonary arterial hypertension receptor research and development research study urinary

项目摘要

DESCRIPTION (provided by applicant): I am a pulmonologist and an Assistant Professor of Pediatrics at Vanderbilt University on the tenure track, with a master degree in patient-oriented research (Master of Science in Clinical Investigation, M.S.C.I.). I am at a critical point in career development, having just completed the master degree program but in need of further training in the disciplines of genetics, biostatistical genetics and epidemiology to achieve my immediate and long-term goals. My five-year goal is to become an expert in genetic epidemiology focused on the causes and mechanisms of heritable pulmonary arterial hypertension (HPAH), with particular emphasis on the sex hormone axis. My long-term goal is to become an independent physician-scientist capable of conducting large patient-oriented research studies and clinical trials that interpret and modulate the interaction of genetic, endogenous and environmental factors to generate health and disease; this includes, but is not limited to, HPAH. To successfully transition to independent extramural funding, I require continued strong mentorship. In this proposal, we delineate a training and research plan that benefits from my experienced mentor group, as well as the collaborative milieu of Vanderbilt and our Pulmonary Hypertension Research Group, to provide a comprehensive mentored educational and research experience. Primary Mentor Dr. James E. Loyd is an expert in the genetic epidemiology of inherited pulmonary diseases, having spent over 25 years developing the well-characterized research cohort that has been so vital to progress made in the study of HPAH, and in the successful transition of physician-scientists to independence. My mentoring committee now includes two new members with expertise in endocrinology, sex hormone metabolism and mentorship, to expand my mentored training influences. This proposal focuses my efforts on the investigation of gender, sex hormones and the development of pulmonary arterial hypertension (PAH). Most types of PAH, including HPAH due to mutations in bone morphogenic protein receptor type 2 (BMPR2)), predominantly affect women for unknown reasons, and our preliminary laboratory data support the central hypothesis that sex hormone variation modifies disease expression in HPAH, because elevated estrogen exposures promote disease. The mentoring, career development, and research plans dovetail to maximize my ability to test this hypothesis in a concise manner and provide a framework for future investigations. To test our hypothesis, we will study sex hormones using association and functional studies with biospecimens from BMPR2 mutation carriers of both genders. Aim 1 will determine whether mediators of estrogen and androgen activity are associated with HPAH. We hypothesize that higher estrogen activity (e.g., as represented by a lower ratio of 2-hydroxyestrogens: 161-hydroxyestrogens) will be associated with increased risk of HPAH and younger age at diagnosis. Aim 2 will determine whether estrogen-enhancing and androgen-diminishing genotypes are associated with HPAH. We hypothesize that estrogen-enhancing and testosterone-diminishing genotypes increase the risk of developing HPAH among BMPR2 mutation carriers. Aim 3 will determine whether sex hormones regulate BMPR2 gene expression in normal pulmonary microvascular endothelial cells and in cell lines derived from BMPR2 mutation carriers. We hypothesize that estrogens will decrease BMPR2 expression, while androgens will increase BMPR2 expression (low BMPR2 expression associates with HPAH). In completing the proposed training and research plans, I will gain the necessary expertise to design, conduct, and analyze multi-disciplinary research studies involving complicated genetic factors. This will allow me to compete effectively for future NIH support and propel me to an independent career in patient-oriented research.

描述（由申请人提供）：我是vanderbilt University的肺科医生和儿科助理教授，并拥有以患者为导向的研究硕士学位（临床研究硕士学位，M.S.C.I.）。我刚刚完成了硕士学位课程，但需要进一步培训遗传学，生物统计学遗传学和流行病学的学科，以实现我的直接和长期目标。我的五年目标是成为遗传流行病学专家，重点是遗传性肺动脉高压（HPAH）的原因和机制，并特别强调了性激素轴。我的长期目标是成为一个独立的医师科学家，能够进行大型的以患者为导向的研究和临床试验，以解释和调节遗传，内源性和环境因素的相互作用，以产生健康和疾病。这包括但不限于HPAH。为了成功地过渡到独立的壁外资金，我需要持续强大的指导。在此建议中，我们划定了一个培训和研究计划，该计划受益于我经验丰富的导师小组，范德比尔特的协作环境和我们的肺动脉高压研究小组，以提供全面的指导教育和研究经验。主要导师詹姆斯·E·洛伊德（James E.医师科学家向独立的过渡。我的指导委员会现在包括两个新成员，具有内分泌学专业知识，性激素代谢和指导，以扩大我的指导培训影响。该提案将我的努力重点放在对性别，性激素和肺动脉高压（PAH）发展的研究上。大多数类型的PAH，包括由于骨形态蛋白受体2型（BMPR2）突变引起的HPAH，主要出于未知原因会影响女性，而我们的初步实验室数据支持了核心假设，即性激素变异改变了HPAH的疾病表达，因为升高了HPAH的表达。雌激素暴露会促进疾病。指导，职业发展和研究计划为了最大程度地提高我以简洁的方式检验这一假设的能力，并为未来的研究提供框架。为了检验我们的假设，我们将使用两种性别的BMPR2突变载体的结合和功能研究研究性激素。 AIM 1将确定雌激素和雄激素活性的介体是否与HPAH相关。我们假设较高的雌激素活性（例如，2-羟基雌激素的比率较低，即161-羟基雌激素）将与诊断时HPAH和年龄较小的风险增加有关。 AIM 2将确定增强雌激素的基因型是否与HPAH相关。我们假设雌激素增强和睾丸激素降低基因型会增加BMPR2突变载体中HPAH的风险。 AIM 3将确定性激素是否调节正常肺微血管内皮细胞和源自BMPR2突变载体的细胞系中的BMPR2基因表达。我们假设雌激素将降低BMPR2的表达，而雄激素将增加BMPR2的表达（低BMPR2表达与HPAH相关）。在完成拟议的培训和研究计划时，我将获得设计，进行和分析涉及复杂遗传因素的多学科研究的必要专业知识。这将使我能够有效地争夺未来的NIH支持，并推动我从事以患者为导向的研究的独立职业。