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，这些证据支持应激反应系统反应性、内脏脂肪组织（VAT）和大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肠易激综合征病理生理有关。使用跨学科的翻译方法，我们将检验VAT增加与下丘脑轴过度活跃相关的假设，这与大脑形态测量学的变化有关，这些变化与性别有关。我们将解决以下具体目标：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，将内脏脂肪，HPA轴活动和区域脑形态学之间的变化联系起来。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下丘脑轴变化和大脑结构和功能变化中的作用。Aim C将研究CRF- oe小鼠中HPA过度活跃、VAT和脂肪因子之间相关性的性别差异，作为早期由CRF遗传驱动的慢性应激改变模型；Aim D将研究男女IBS患者中HPA轴与VAT积累和循环脂肪因子与区域脑结构和静息状态功能变化之间的相关性。我们将在这一应用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，以及基于定量MRI或CT的啮齿动物和人类增值税评估方法。转基因动物将用于测试脂肪因子和CRF/CRFR1信号通路在该系统中的具体作用。本项目中啮齿类动物模型和人类研究的使用与项目1和项目3相辅相成，项目1研究了肠易激综合征患者HPA轴失调的特征，项目3使用多模态脑成像、先进的数学建模/系统生物学方法根据不同的内表型集群识别肠易激综合征患者亚型。提出的临床前和临床研究的结果应该能够明确地解决关于过度VAT积累和大脑变化的病理生理作用以及与IBS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.