HPA Axis-Dependent Visceral Adipose tissue and brain changes in IBS and related

该建议基于广泛的临床前和临床证据，支持应激反应系统反应性、内脏脂肪组织（VAT）和脑结构和功能变化之间的复杂相互作用，这些变化可能与胃肠道症状和IBS病理生理学相关。使用跨学科的翻译方法，我们将测试的假设，即增加增值税相关的HPA轴的过度活跃，是与脑形态学的变化与性别相关的差异，在这些改变。我们将致力于以下具体目标：目标A将在成年雄性和雌性大鼠的慢性不可预测的压力的啮齿动物模型中，内脏肥胖、HPA轴活性和局部脑形态学之间的变化相关联。目的B将描述内脏脂肪产物在应激诱导的雄性和雌性啮齿动物HPA轴变化和脑结构和功能变化中的作用。目的C将在CRF-OE小鼠中研究HPA过度活动、VAT和脂肪因子之间的相关性的性别差异，CRF-OE小鼠作为自生命早期以来由CRF遗传驱动的慢性应激改变的模型。目的D将在男性和女性IBS患者中将HPA轴与VAT积累和循环脂肪因子与局部脑结构和静息状态功能变化相关联。我们将在本申请的许多方面采用几种新颖的方法和最先进的技术，包括啮齿动物脑MRI、人类多模态脑成像以及啮齿动物和人类基于MRI或CT的定量VAT评估方法。转基因动物将用于测试脂肪因子和CRF/CRFR 1信号通路在该系统中的特定作用。在该项目中使用啮齿动物模型和人类研究是互补的，并且与项目1和项目3相关，项目1表征IBS患者中的HPA轴失调，项目3使用多模式脑成像，先进的数学建模/系统生物学方法来基于不同的内在表型簇鉴定IBS患者亚型。拟议的临床前和临床研究的结果应该能够明确地解决增值税过度积累和大脑变化的病理生理作用以及与IBS的关系的主要假设。

This proposal is based on extensive preclinical and clinical evidence supporting complex interactions between alterations in the stress response system reactivity, visceral adipose tissue (VAT), and brain structural and functional changes that might be related to gastrointestinal symptoms and IBS pathophysiology. Using an interdisciplinary translational approach, we will test the hypothesis that increased VAT related to hyperactivity of the HPA axis, is associated with changes in brain morphometry with sex related differences in these alterations. We will adress the following specific aims: Aim A will correlate changes between visceral adiposity, HPA axis activity and regional brain morphology in a rodent model of chronic unpredictable stress in adult male and female rats. Aim B will characterize the role of visceral fat products in stress-induced changes in the HPA axis and brain structural and functional changes in male and female rodents. Aim C will study sex differences in the correlation between HPA overactivity, VAT and adipokines in CRF-OE mice as a model of chronic alterations of stress, genetically driven by CRF since early life, Aim D will correlate HPA axis with VAT accumulation and circulating adipokines to regional brain structural and resting state functional changes in male and female IBS patients. We will employ several novel methodologies and state-of-the-art technologies in many aspects of this application, including rodent brain MRI, multimodal brain imaging in humans, and quantitative MRI-or CT based VAT assessment methods in rodents and humans. Transgenic animals will be used to test the specific role of adipokines and of the CRF/CRFR1 signaling pathways in this system. The use of rodent models and human studies in this project are complementary and related to project 1 which characterizes HPA axis dysregulation in IBS patients and to Project 3 which uses multimodal brain imaging, advanced mathematical modeling/systems biological approaches to identify IBS patients subtypes based on distinct endophenotype clusters. The results of the proposed preclinical and clinical studies should be able to unequivocally address the main hypotheses on the pathophysiological role of excessive VAT accumulation and brain changes and relationship to IBS.