Dysregulation of FSH in Obesity: Functional and Statistical Analysis

 描述（由申请人提供）：在美国，近三分之一的育龄妇女肥胖。由于母亲肥胖会影响后代的健康， 更好地理解驱动这些影响的机制。目前尚不清楚潜在的病理生理学是否与异常的下丘脑-垂体动力学、异常的卵巢环境或两者有关。肥胖与垂体促黄体生成激素（LH）和FSH输出减少、卵泡生成不足以及卵巢类固醇和蛋白质产生减少有关。尽管缺乏限制和正常的垂体FSH储备，但FSH分泌持续不足仍无法解释。FSH以脉冲方式间歇性分泌，这对下丘脑-垂体-卵巢（HPO）轴的调节很重要。FSH脉冲式分泌的特征一直具有挑战性。我们推测，仍然存在缺乏明确性的一个原因是，目前的分析方法未能适当地表征FSH的激素分泌动力学及其反馈。 最重要的目标是使用多学科方法来定义FSH-卵巢相互作用的基本特征。我们建立在（1）我们现有的贝叶斯方法来建模脉动激素，以开发一个生物学相关的和灵活的模型，和（2）转基因FSH小鼠模型显示，脉动FSH分泌显着增强卵巢功能。 AIM 1重点展示了新的关节模型如何利用LH脉冲的更清晰信息来阐明FSH脉冲。两种激素的脉冲位置和幅度之间的关联将用于区分FSH的组成性分泌和脉冲性分泌。我们将以一种具有成本效益的方式利用PI先前进行的NIH资助的肥胖研究的现有实验数据。在AIM 2中，我们将确定外源性FSH脉冲式给药是否会导致肥胖妇女卵巢激素显著增加。在GnRH拮抗剂阻断前后，将在接受频繁采血研究的肥胖和正常体重女性中测量系列β-受体结合素B和E2水平。目的3将在转基因小鼠模型中确定FSH脉冲特征和饮食诱导的肥胖对FSH及其促分泌素的影响。将使用连续血液采样和同时测量低体积小鼠血清中LH和FSH的多重测定法。我们还将测量FSH反应性卵巢基因如何受到影响，进行生育力分析，并测试卵母细胞质量。 最终，我们预计我们的研究结果将确定HPO轴（中央与卵巢）的组成部分，主要影响肥胖妇女的激素失调。确定一个方向将告知未来的研究之间的相互作用改变HPO动力学和可能的分子机制。我们也将开发一个通用的分析框架，以澄清任何相关激素的脉冲分泌。

 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.