Pathogenesis of Intestinal Intussusception and the Role of Rotavirus Infection

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 Recently, a live attenuated rotavirus vaccine that was licensed for use in the United States was withdrawn because of an unexpected association of this vaccine with intussusception.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