Effects of edema on cadherins in small intestine

描述（由申请人提供）： 间质性水肿，通常与腹部手术或创伤有关，已被证明会导致肠道功能障碍，包括减少运输。因此，肠水肿的发展对ICU和术后患者的结局具有显著的负面影响。初步数据表明，水肿破坏了细胞间粘附分子钙粘蛋白的信号传导。一般假设是水肿诱导组织重塑，导致器官功能障碍。目的是在细胞和分子水平上研究水肿的影响，以了解水肿诱导功能障碍的机制。在这个提议中要解决的具体假设是，水肿破坏了肠平滑肌中钙粘蛋白介导的细胞-细胞接触，导致肠转运减少。第一个具体的目的是研究在体内使用静脉高压大鼠模型肠水肿对钙粘蛋白信号转导的影响。第二个具体目标是在大鼠肠水肿模型中将钙粘蛋白信号传导的变化与肠收缩力的变化相关联。第三个具体目标是利用肠平滑肌细胞培养模型来阐明钙粘蛋白在平滑肌收缩中的作用。第四个具体目标是确定水肿诱导钙粘蛋白改变的机制。候选人将获得细胞粘附的一个相对较新的领域的专业知识，同时追求她在流体平衡和微血管研究的长期研究兴趣。赞助者和共同赞助者都是各自领域的专家，在培训青年科学家方面有着良好的记录。研究计划和培训计划将帮助候选人在微血管研究组内建立独立和互补的研究计划。KO 1奖将通过支持研究培训活动促进候选人的独立发展，同时完成拟议的研究，包括肠道功能，平滑肌生物学和钙粘蛋白/连环蛋白信号传导领域的专家指导，参加与她的研究领域相关的研究会议，并参加赠款写作和伦理课程。

DESCRIPTION (provided by applicant): Interstitial edema, often associated with abdominal surgery or trauma, has been shown to cause intestinal dysfunction including decreased transit. Thus, intestinal edema development has significant negative impact on the outcome of ICU and post-surgical patients. Preliminary data suggests that edema disrupts signaling by the cell-cell adhesion molecule, cadherin. The general hypothesis is that edema induces tissue remodeling that leads to organ dysfunction. The goal is to investigate the effects of edema at the cellular and molecular level in order to understand the mechanism by which edema induces dysfunction. The specific hypothesis to be addressed in this proposal is that edema disrupts cadherin-mediated cell-cell contacts in intestinal smooth muscle causing a decrease in intestinal transit. The first specific aim is designed to examine the effects of intestinal edema on cadherin signaling in vivo using a venous hypertension rat model. The second specific aim is to correlate changes in cadherin signaling with changes in intestinal contractility in the rat intestinal edema model. In the third specifc aim, an intestinal smooth muscle cell culture model will be used to elucidate the role of cadherins in smooth muscle contraction. The fourth specific aim is designed to determine the mechanisms by which edema induces alterations in cadherins. The candidate will gain expertise in a relatively new area of cell adhesion while pursuing her long term research interests in fluid balance and microvascular research. The sponor and co-sponsors are experts in their respective fields and have proven track records in training young scientists. The research proposal and training plan will help the candidate establish an independent and complementary research program within the Microvascular Research Group. The KO1 award will facilitate the candidate's progression to independence by supporting the research training activities while the proposed research is being completed including mentoring by experts in the fields of intestinal function, smooth muscle biology, and cadherin/catenin signaling, attending research conferences relative to her area of research, and taking grant writing and ethics courses.