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

• 批准号: 7989599
• 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
• 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/7989599
• 关键词: Adult; Affect; Age; Androgens; BMPR2 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; 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; Hand; Health; High Prevalence; Histopathology; Hydroxyestrones; In Vitro; Inherited; Investigation; Laboratories; Lung; Lung diseases; Mass Spectrum Analysis; Master of Science; Master' s Degree; Mediating; Mediator of activation protein; Mentors; Mentorship; Metabolism; Mutation; Odds Ratio; Pathogenesis; Patients; Pediatrics; Pharmacologic Substance; Physicians; Pregnancy; Prevalence; Pulmonary Hypertension; Reporting; Research; Research Training; Risk; Risk Factors; Role; 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; public health relevance; pulmonary arterial hypertension; research study; urinary

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. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension (PAH) predominantly affects women for unknown reasons. The risk of gender, association of PAH with pregnancy and estrogen- containing pharmaceuticals, and our preliminary experimental data implicate estrogen in disease pathogenesis. This project has implications for PAH and other pulmonary diseases with a gender discrepancy by identifying and exploring genetic risk factors for elevated estrogen exposures and how they promote disease.

描述（由申请人提供）：我是一名肺科医生，也是范德比尔特大学的终身教授，拥有以患者为中心的研究硕士学位（临床研究理学硕士，MSCI）。我正处于职业发展的关键时刻，刚刚完成硕士学位课程，但需要在遗传学、生物统计遗传学和流行病学学科上进一步培训，以实现我的近期和长期目标。我的五年目标是成为遗传流行病学专家，专注于遗传性肺动脉高压（HPAH）的病因和机制，特别是性激素轴。我的长期目标是成为一名独立的医师科学家，能够进行大型以患者为导向的研究和临床试验，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。为了成功过渡到独立的外部资助，我需要持续的强有力的指导。在这份提案中，我们制定了一项培训和研究计划，该计划受益于我经验丰富的导师团队以及范德比尔特大学和我们的肺动脉高压研究小组的协作环境，以提供全面的指导教育和研究经验。主要导师 James E. Loyd 博士是遗传性肺病遗传流行病学专家，他花了 25 年多的时间开发了特征明确的研究队列，这对于 HPAH 研究的进展以及成功的医师科学家向独立的转变。我的指导委员会现在包括两名在内分泌学、性激素代谢和指导方面具有专业知识的新成员，以扩大我指导的培训影响力。该提案将我的工作重点放在性别、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 2 型骨形态发生蛋白受体 (BMPR2) 突变引起的 HPAH，主要影响女性，原因不明，我们的初步实验室数据支持以下中心假设：性激素变异会改变 HPAH 的疾病表达，因为雌激素暴露会促进疾病。指导、职业发展和研究计划相互配合，以最大限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，我们将使用来自两性 BMPR2 突变携带者的生物样本进行关联和功能研究来研究性激素。目标 1 将确定雌激素和雄激素活性介质是否与 HPAH 相关。我们假设较高的雌激素活性（例如，以较低的 2-羟基雌激素：161-羟基雌激素的比例为代表）将与 HPAH 风险增加和诊断时年龄较小相关。目标 2 将确定雌激素增强和雄激素减少基因型是否与 HPAH 相关。我们假设雌激素增强和睾酮减少的基因型会增加 BMPR2 突变携带者患 HPAH 的风险。目标 3 将确定性激素是否调节正常肺微血管内皮细胞和 BMPR2 突变携带者衍生的细胞系中的 BMPR2 基因表达。我们假设雌激素会降低 BMPR2 表达，而雄激素会增加 BMPR2 表达（低 BMPR2 表达与 HPAH 相关）。在完成拟议的培训和研究计划时，我将获得必要的专业知识来设计、进行和分析涉及复杂遗传因素的多学科研究。这将使我能够有效地竞争未来 NIH 的支持，并推动我在以患者为导向的研究领域走向独立的职业生涯。 公共卫生相关性：肺动脉高压 (PAH) 主要影响女性，原因不明。性别风险、PAH 与妊娠和含雌激素药物的关系以及我们的初步实验数据表明雌激素与疾病发病机制有关。该项目通过识别和探索雌激素暴露升高的遗传风险因素及其如何促进疾病，对 PAH 和其他具有性别差异的肺部疾病产生影响。