Pathogenesis of Intestinal Intussusception and the Role of Rotavirus Infection

描述(申请人提供)：肠套叠是指肠道的一段内陷到相邻的肠段。尽管肠套叠是幼儿肠梗阻最常见的原因，并可发生在任何年龄，但由于缺乏动物模型，影响肠套叠发展的因素尚不清楚。风险因素既包括宿主因素，也包括环境因素，包括感染性因素。最近，一种在美国获得使用许可的减毒活轮状病毒疫苗被撤回，因为这种疫苗与肠套叠意外地联系在一起。有趣的是，我们最近发现轮状病毒感染可以增强内毒素诱导的小鼠肠套叠，从而建立了第一个病毒性肠套叠动物模型，并为轮状病毒疫苗与肠套叠的相关性提供了潜在的解释。为了探讨肠套叠的发病机制(S)以及病毒感染与肠套叠的关系，本研究提出利用脂多糖和轮状病毒-脂多糖增强的肠套叠小鼠模型，[1]利用核磁共振确定肠套叠的动力学，并确定肠套叠是否是由于小肠收缩活动的节段性改变所致，[2]研究肠上皮细胞TLR4信号在肠套叠发生发展中的作用。我们在轮状病毒动物模型和啮齿动物核磁共振成像方面的丰富经验为解决这些重要问题提供了框架。这些研究的完成将提供一种新的病毒诱导的肠套叠模型，并建立一种基于MRI的方法来研究肠道运动障碍作为多参数相互作用的函数。此外，这项工作将为轮状病毒疫苗和肠套叠之间的联系提供见解。

DESCRIPTION (provided by applicant): Intestinal intussusception is an invagination of one segment of the intestine into an adjacent segment. Although intussusception is the most common cause of life-threatening obstruction of the intestine in young children and can occur at any age, the factors that influence the development of intussusception are poorly understood due to a lack of animal models. Risk factors include both host and environmental factors, including infectious agents. Recently, a live attenuated rotavirus vaccine that was licensed for use in the United States was withdrawn because of an unexpected association of this vaccine with intussusception. Interestingly, we have recently discovered that rotavirus infection can enhance LPS-induced intussusception in mice, thus establishing the first animal model of viral induced intussusception and providing a potential explanation for the association of the rotavirus vaccine with intussusception. To begin to identify the mechanism(s) of intussusception and the associations of a viral infection with intussusception, this application proposes to utilize the mouse models of LPS and rotavirus-LPS enhanced intussusception to examine both gross alterations in intestinal motility as well as molecular changes occurring in the epithelium by [1] utilizing MRI to determine the kinetics of intussusception and to determine whether intussusception results from segmental changes in small intestinal contractile activity, and [2] examining the contribution of TLR4 signaling by epithelial cells to the development of intussusception. Our extensive experience with rotavirus animal models and MRI imaging in rodents provides the framework to address these important questions. Completion of these studies will provide a new model of viral induced intussusception and the establishment of an MRI based approach to study dysmotility as a function of multi-parameter interactions in the intestine. In addition, this work will provide insights into to the link between the rotavirus vaccine and intussusception.