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.
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