Variations in estrogen exposures may modify pulmonary arterial hypertension

描述（由申请人提供）：我是范德比尔特大学的肺病学家和儿科助理教授，拥有以患者为导向的研究硕士学位（临床研究科学硕士，M.S.C.I.）。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等学科进一步培训，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）的原因和机制，特别强调性激素轴。我的长期目标是成为一名独立的医生科学家，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。为了成功地过渡到独立的校外资金，我需要持续强大的指导。在本提案中，我们描绘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，以及范德比尔特和我们的肺动脉高压研究小组的合作环境，以提供全面的指导教育和研究经验。导师：James E. Loyd是遗传性肺部疾病遗传流行病学专家，他花了25年多的时间开发了一个特征鲜明的研究队列，该队列对HPAH研究取得的进展以及医生-科学家向独立的成功过渡至关重要。我的指导委员会现在包括两名新成员，他们在内分泌学、性激素代谢和指导方面有专业知识，以扩大我的指导培训影响力。本研究主要集中在性别、性激素与肺动脉高压发生发展的关系上。大多数类型的PAH，包括由于骨形态发生蛋白受体2（BMPR 2）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性激素变化改变HPAH疾病表达的中心假设，因为雌激素暴露升高会促进疾病。指导，职业发展和研究计划相吻合，以最大限度地提高我的能力，以简洁的方式测试这一假设，并为未来的调查提供一个框架。为了验证我们的假设，我们将使用来自两种性别的BMPR 2突变携带者的生物标本的关联和功能研究来研究性激素。目的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，如较低的2-羟基雌激素：161-羟基雌激素的比率所代表的）将与HPAH的风险增加和诊断时年龄较轻相关。目的2将确定是否雌激素增强和雄激素减少基因型与HPAH。我们假设雌激素增强和睾酮减少基因型增加BMPR 2突变携带者发生HPAH的风险。目的3将确定性激素是否调节正常肺微血管内皮细胞和BMPR 2突变携带者衍生的细胞系中BMPR 2基因的表达。我们假设雌激素会降低BMPR 2的表达，而雄激素会增加BMPR 2的表达（BMPR 2的低表达与HPAH相关）。在完成拟议的培训和研究计划，我将获得必要的专业知识，设计，进行和分析涉及复杂的遗传因素的多学科研究。这将使我能够有效地竞争未来的NIH支持，并推动我在以患者为导向的研究中独立的职业生涯。

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.