The long term goal of this proposal is to understand the pathogenesis of surgical necrotizing enterocolitis (NEC), the most frequent and lethal gastrointestinal disorder affecting the stressed, preterm infant. Although initially affecting the intestine, patients with NEC may rapidly develop systemic sepsis and multi-system organ failure and death from overwhelming septic shock. Current thinking indicates that the development of NEC reflects the effects of systemic stress causing a breakdown of the intestinal barrier. This leads to the translocation of bacteria and lipopolysaccharide (LPS), which is recognized on immune cells and enterocytes by Toll Like Receptor 4 (TLR4). We now propose that activation of TLR4 by LPS leads to sepsis and further intestinal injury, characteristic of NEC. Healing of the injured intestinal mucosa typically occurs through epithelial restitution, in which healthy enterocytes migrate towards the denuded mucosa. We have developed a rodent model that mimics human NEC, and have shown that intestinal restitution is significantly impaired in animals with NEC compared with controls. Strikingly, mice with mutations in TLR4 have significantly reduced severity of NEC as compared to wild-type littermates. In vitro, enterocyte migration is regulated by RhoA and integrins, and treatment of enterocytes with LPS leads to a significant inhibition in enterocyte migration through the activation of RhoA and increased cell-matrix adhesion. We now hypothesize that TLR4 plays a critical role in the pathogenesis of NEC through the activation of RhoA and integrins and impaired intestinal restitution. To test this hypothesis, we propose:
Aim 1 To assess the effects of LPS on the expression and activity of TLR4 in enterocytes in vitro and in vivo.
Aim 2. To determine whether TLR4 signaling is necessary for the effects of LPS on RhoA activation and enterocyte migration and to determine the signaling pathways involved.
Aim 3. To determine whether TLR4 is required for the induction of necrotizing enterocolitis in vivo through effects on RhoA activity and enterocyte migration. By testing the hypothesis that TLR4 signaling plays a critical role in the pathogenesis of NEC, we propose to understand the principal steps that lead to the development of this devastating illness, and to identify novel treatment strategies for these fragile patients. ? ? ?
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