Gut mucosal injury occurs commonly in patients with inflammatory bowel disease (IBD) and critical surgical disorders such as trauma, massive thermal injuries, sepsis, and emergent surgical operations. Effective therapies to preserve the integrity of the intestinal epithelium and enhance recovery of damaged mucosa in patients with critical illnesses are limited; because of poorly understood mechanisms underlying gut mucosal injury and repair. Achieving a better understanding of the pathogenesis of mucosal injury/erosions and developing effective therapies to protect the epithelium from injury and promote repair after wounding in patients with critical illness are still urgent challenges. Long noncoding RNAs (lncRNAs) regulate a variety of biological functions and are intimately involved in the pathogenesis of diverse human diseases. Although emerging evidence increasingly points to the importance of lncRNAs in maintaining gut epithelial integrity, their exact roles in the mechanisms regulating intestinal mucosal repair after injury remain largely unknown. Recent studies also reveal that mitochondrial metabolism is essential for maintaining intestinal epithelial integrity, while targeted deletion of mitochondrial prohibitin-1 and Hsp60 causes murine ileitis. By using genome-wide profile analysis, we identified hundreds of lncRNAs, including uc.230 and growth arrest specific 5 (GAS5), which are differentially expressed in the intestinal mucosa in response to pathological stress. Our preliminary studies indicate that a) after wounding, ulcerative colitis (uc).230 is required for intestinal mucosal repair whereas GAS5 induction delays epithelial recovery; and b) silencing uc.230 or overexpressing GAS5 results in mitochondrial dysfunction in intestinal epithelial cells. Based on our exciting observations, we HYPOTHESIZE that uc.230 and GAS5 regulate intestinal mucosal repair after injury by altering mitochondrial function. Three specific aims are designed to test this hypothesis: 1) to define the exact roles of uc.230 and GAS5 in regulating intestinal mucosal repair after injury in critical pathological conditions; 2) to determine whether uc.230 and GAS5 modulate injury-induced intestinal mucosal regeneration by altering mitochondrial metabolism; and 3) to define the mechanisms whereby cellular levels of uc.230 and GAS5 are regulated in response to pathological stress. Completion of these specific aims will provide a substantial conceptual advance by linking lncRNA-mediated changes in mitochondrial metabolism with injury-induced regeneration of the intestinal epithelium and will create a fundamental basis for developing novel therapies to preserve intestinal epithelial integrity and enhance mucosal repair in the clinical setting for Veterans with critical illnesses.