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

这一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)的变化与可能与胃肠道症状和IBS病理生理有关的脑结构和功能变化之间的复杂交互作用。使用跨学科的转换方法，我们将检验这一假设，即增值税增加与HPA轴的过度活动有关，与大脑形态计量学的变化有关，这些变化与性别有关。我们将提出以下具体目标：目的A将在成年雄性和雌性大鼠慢性不可预测应激的啮齿动物模型中，将内脏肥胖、HPA轴活动和局部脑形态之间的变化联系起来。目的研究内脏脂肪产物在应激引起的雄性和雌性啮齿动物HPA轴改变以及脑结构和功能改变中的作用。目的C将研究CRF-OE小鼠HPA过度活动、VAT与脂肪因子相关性的性别差异，作为CRF早期遗传驱动的慢性应激改变模型。目的D将HPA轴与VAT蓄积及循环脂肪因子与男女IBS患者局部脑结构和静息状态功能变化相关联。我们将在这一应用的许多方面采用几种新的方法和最先进的技术，包括啮齿动物的脑MRI、人类的多模式脑成像，以及啮齿动物和人类的基于MRI或CT的增值税定量评估方法。转基因动物将被用来测试脂肪因子和CRF/CRFR1信号通路在这个系统中的特定作用。在本项目中，啮齿动物模型和人类研究的使用是互补的，与项目1和项目3相关，项目1描述了IBS患者的HPA轴失调，项目3使用多模式脑成像、先进的数学建模/系统生物学方法根据不同的内表型簇识别IBS患者的亚型。拟议的临床前和临床研究结果应该能够明确提出关于增值税过度积累和脑变化的病理生理作用以及与IBS的关系的主要假说。

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.