Dysregulation of FSH in Obesity: Functional and Statistical Analysis

 描述(申请人提供)：在美国，近三分之一的育龄妇女患有肥胖症。由于母亲肥胖会影响后代的健康，因此迫切需要 更好地了解驱动这些影响的机制。目前尚不清楚其潜在的病理生理学机制是否与下丘脑-垂体动力学异常、卵巢环境异常或两者都有关。肥胖与脑下垂体黄体生成素(LH)和卵泡刺激素(FSH)的输出减少、卵泡发育不足以及卵巢类固醇和蛋白质的产生减少有关。尽管缺乏节制和正常的垂体FSH储备，但FSH分泌持续不足的原因仍不清楚。FSH以脉冲的形式间歇性分泌，对下丘脑-垂体-卵巢(HPO)轴的调节非常重要。卵泡刺激素的脉动性分泌一直是一个具有挑战性的特征。我们假设，缺乏清晰度的一个原因仍然存在，那就是目前的分析方法不能适当地表征FSH及其反馈的激素分泌动力学。最重要的目标是使用多学科方法定义FSH-卵巢相互作用的基本特征。我们建立在(1)我们现有的模拟脉动激素的贝叶斯方法的基础上，以开发一个生物学上相关的和灵活的模型，以及(2)转基因FSH小鼠模型，显示脉动的FSH分泌显著增强卵巢功能。目标1重点展示了新的联合模型如何利用关于促黄体生成素脉冲的更清晰的信息来澄清促卵泡激素脉冲。这两种激素的脉冲位置和幅度之间的关系将被用来区分FSH的结构性分泌和脉动性分泌。我们将以经济高效的方式利用PI以前由NIH资助的肥胖症研究中的现有实验数据。在AIM 2中，我们将确定以脉冲式方式给予外源性FSH是否会导致肥胖女性卵巢激素显著增加。在GnRH拮抗剂阻断前后，进行频繁采血研究的肥胖和正常体重妇女的系列抑制素B和E2水平将被检测。目的3将在转基因小鼠模型中确定FSH的脉冲特征以及饮食诱导肥胖对FSH及其促分泌物的影响。将使用连续采血和同时测定少量小鼠血清中促黄体生成素和促卵泡生成素的多重试验。我们还将测量对FSH反应的卵巢基因将如何受到影响，进行生育分析，并测试卵母细胞的质量。最终，我们预计，我们的结果将精确定位HPO轴的组成部分(中央与卵巢)，这主要是肥胖女性激素失调的影响因素。方向的确定将为未来研究改变的HPO动力学和可能的分子机制之间的相互作用提供信息。我们还将开发一个通用的分析框架，以澄清任何相关激素的脉动性分泌。

 DESCRIPTION (provided by applicant): In the United States, nearly one in three women of childbearing age is obese. As maternal obesity impacts the health of offspring, it is imperative to obtain a better understanding of the mechanisms that drive these influences. It remains unclear whether the underlying pathophysiology is related to abnormal hypothalamic- pituitary dynamics, abnormal ovarian environment, or both. Obesity is associated with decreased pituitary output of luteinizing hormone (LH) and FSH, inadequate folliculogenesis and reduced ovarian steroid and protein production. The persistent deficit in FSH secretion, despite the lack of restraint and normal pituitary FSH reserve, remains unexplained. FSH is secreted intermittently in pulses, which are important for hypothalamic-pituitary-ovarian (HPO) axis regulation. FSH pulsatile secretion has been challenging to characterize. We hypothesize that one reason a lack of clarity still exists is that current analytic methods fail to appropriately characterize the hormone secretion dynamics of FSH and its feedback. The overriding objective is to define essential characteristics of FSH-ovarian interactions using a multi- disciplinary approach. We build upon (1) our existing Bayesian approaches to modeling pulsatile hormones to develop a biologically relevant and flexible model, and (2) transgenic FSH mouse model showing that pulsatile FSH secretion dramatically enhances ovarian function. AIM 1 focuses on showing how new joint models leverage the clearer information about LH pulses to clarify FSH pulses. Associations between pulse locations and amplitudes of both hormones will be used to differentiate between constitutive and pulsatile secretion of FSH. We will utilize existing experimental data from the PI's previously conducted NIH-funded obesity studies in a cost-effective way. In AIM 2, we will determine if exogenous FSH administered in a pulsatile fashion results in a significant increase of ovarian hormones in obese women. Serial inhibin B and E2 levels will be measured in obese and normal weight women undergoing frequent blood sampling studies before and after GnRH antagonist blockade. AIM 3 will determine the FSH pulse characteristics and effects of diet-induced obesity on FSH and its secretagogues in a transgenic mouse model. Serial blood sampling and a multiplex assay that simultaneously measures LH and FSH in low volumes of mouse serum will be used. We will also measure how FSH-responsive ovarian genes would be affected, perform fertility analysis, and test the oocyte quality. Ultimately, we anticipate that our results will pinpoint the component of the HPO axis (central vs. ovary) that is primarily affected in hormonal dysregulation in obese women. Identification of a direction will inform future studies of interactions between altered HPO dynamics and possible molecular mechanisms. We will also develop a general analytic framework to clarify pulsatile secretion in any linked hormones.