Necrotizing enterocolitis (NEC), a major cause of morbidity and mortality in neonatal intensive care units, is a disease for which there is currently no medical treatment. Treatment of infants that develop NEC is solely supportive. Indications for surgical intervention include bowel perforation and/or signs of bowel necrosis. Infants with NEC who require surgical intervention are at high risk for poor neurodevelopmental and functional outcomes. Exciting new mechanisms regarding the pathogenesis of NEC have recently become known and nitric oxide (NO) dysregulation appears to play a major role in the development of NEC. NO dysregulation can lead to reactive nitrogen species, leading to cellular protein oxidation and DNA damage. Poly(ADP-ribose) polymerase (PARP) is up-regulated in response to these changes and can lead to cellular depletion of NAD+ and ATP inhibiting cell survival pathways. We have previously shown that intestinal O2 consumption is altered in human NEC secondary to nitric oxide synthase 2 (NOS2) induction. When there are decreased cellular energy stores in the presence of DNA damage, PARP will cause the cell to preferentially undergo a necrotic cell death pathway rather than DNA repair or apoptosis. Necrotic cells release proinflammatory mediators into surrounding tissues, propagating injury. Thus, PARP-1 acts as a gatekeeper between cell survival, apoptosis, and necrosis. The studies described in the present proposal are designed to test the overall working hypothesis that NO dysregulation in the intestinal epithelial cell during NEC leads to marked PARP-1 activation that in turn leads to altered epithelial cell function and bowel necrosis.
Specific Aim 1 is to define the downstream consequences of PARP-1 activation using an in vitro model of isolated human immature intestinal epithelial cell injury.
Specific Aim 2 is to determine therapeutic value and mechanistic aspects of PARP-1 antagonism in an in vivo model of NEC. An important feature of this application is the investigation of nicotinamide (a water soluble B vitamin known to inhibit PARP) as a potential therapeutic agent for NEC. These studies will use relevant human fetal intestinal epithelial cells, animal models of newborn intestinal injury and specimens from the non-necrotic resection margins of human newborn surgical NEC specimens to test our working hypothesis.
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