Pathogenesis of Intestinal Intussusception and the Role of Rotavirus Infection

描述（由申请人提供）：肠套叠是一段肠内陷到相邻肠段。虽然肠套叠是幼儿危及生命的肠梗阻的最常见原因，并且可以发生在任何年龄，但由于缺乏动物模型，对影响肠套叠发展的因素知之甚少。风险因素包括宿主和环境因素，包括感染因子。最近，一种减毒活轮状病毒疫苗在美国被许可使用，但由于该疫苗与肠套叠的意外关联而被撤回。有趣的是，我们最近发现轮状病毒感染可以增强LPS诱导的小鼠肠套叠，从而建立了第一个病毒诱导肠套叠的动物模型，并为轮状病毒疫苗与肠套叠的关联提供了潜在的解释。为了开始确定肠套叠的机制以及病毒感染与肠套叠的关系，该申请提出利用LPS和轮状病毒-LPS增强的肠套叠的小鼠模型来检查肠运动的总体改变以及上皮中发生的分子变化，利用MRI确定肠套叠的动力学并确定肠套叠是否由小肠收缩活动的节段性变化引起，以及[2]检查上皮细胞的TLR 4信号传导对肠套叠发展的贡献。我们在啮齿动物轮状病毒动物模型和MRI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肠套叠模型，并建立一种基于MRI的方法来研究肠内多参数相互作用对动力障碍的影响。此外，这项工作将提供深入了解轮状病毒疫苗和肠套叠之间的联系。

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 Recently, a live attenuated rotavirus vaccine that was licensed for use in the United States was withdrawn because of an unexpected association of this vaccine with intussusception.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.