Patients with critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations are commonly complicated with acute gut mucosal injury and bleeding, but effective therapies to preserve the epithelial integrity are limited to date. Disrupton of the gut epithelial integrity causes sepsis and in some instances acts as the trigger that drives multiple organ dysfunction syndrome (MODS), a leading cause of death in critically ill patients. Early rapid epithelial restitution is an important primary repair modality in the gut mucosa and plays a critical role in maintaining mucosal integrity, but the exact mechanism underlying this process remains unclear. Epithelial restitution occurs as a consequence of cell migration over the damaged area after superficial injury, a process that is independent of cell proliferation. Our previous studies have demonstrated that small GTPases are crucial for normal gut mucosal restitution after acute injury. However, the exact signals initiating the activation of GTPases aftr injury remain elusive and are the focus of this renewal application. a4 is a novel PP2A associated protein and is involved in many aspects of cell functions including cell motility. Our preliminary results indicate that a) early rapid mucosal restitution following injury was associate with an induction in a4 expression in mice; b) ectopic overexpression of the a4 gene enhanced epithelial restitution after wounding, whereas a4 silencing or inhibition of its downstream target -PIX repressed mucosal repair through a process involving the GTPase Rac1; and c) polyamines are necessary for normal expression of a4. Based on these exciting preliminary observations, we HYPOTHESIZE that a4 stimulates intestinal epithelial restitution after acute mucosal injury by altering PP2A/-PIX-mediated Rac1 signaling.
Three specific aims are proposed to test the hypothesis: 1) to determine the pattern and role of a4 in gut epithelial restitution after acute mucosal injury in critical surgical conditions; 2) to analyze the mechanism by which a4 regulates IEC migration during epithelial restitution; and 3) to define the cellular signaling pathways regulating a4 expression after mucosal injury, with a particular focus on cellular polyamines. Completion of this study will create a fundamental base for development of new therapies to enhance early rapid mucosal repair and preserve gut epithelial integrity under critical surgical conditions.
Patients with critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations are commonly complicated with gut mucosal injury and bleeding, but effective therapies to preserve the epithelial integrity are limited to date. Delayed mucosal repair causes disruption of mucosal epithelial integrity, thus contributing to the morbidity and mortality. Although mucosal restitution is critical for maintaining epithelial integrity during criical surgical stress, the exact mechanism underlying this process remains unclear. Goal of this study is to define the cellular and molecular mechanism by which damaged mucosa is rapidly repaired by testing a novel hypothesis that a4, an important PP2A associated protein, plays a role in the regulation of gut mucosal restitution. Completion of this study will provide a fundamental base for development of new therapies to protect the gut mucosa in critical surgical illnesses and facilitate repair of damaged mucosa in our Veteran patients.
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