Intestinal Mucosal Growth in Health and Surgical Diseases

Abstract Inhibition of intestinal mucosal growth occurs commonly in various critical surgical disorders, particularly in patients who undergo massive gastrointestinal surgical resections and are then supported with total parenteral nutrition (TPN). Disrupted mucosal renewal impairs gut barrier dysfunction and leads to sepsis and, in some instances, multiple organ dysfunction syndrome and death. Effective therapies to preserve the intestinal epithelial integrity in patients with critical surgical illnesses are limited, as the mechanisms that regulate gut mucosal renewal in stressful environments are poorly understood. With on-going support for this project, our group was the first to implicate RNA-binding proteins (RBPs) and long noncoding RNAs (lncRNAs) in gut mucosal growth and to show that dysregulation of RBP HuR and lncRNA uc.173 impairs epithelial renewal, compromises epithelial host defenses, and disrupts the intestinal barrier. However, it remains unknown how dysregulated HuR and uc.173 affect growth of the intestinal mucosa and how these findings can be exploited to benefit patients with critical surgical illnesses. Rapid self-renewal of the intestinal mucosa is driven by intestinal stem cells (ISCs) located at the crypt base. Paneth cells (PCs) constitute the niche for ISCs in the small intestine and provide multiple secreted (WNT, EGF) and surfaced- bound (Notch ligand) niche signals essential for ISC maintenance and function. Mitochondrial homeostasis is essential for sustaining the PC/ISC niche, whereas disrupted mitochondrial function leads to PC defects and ileitis. Our preliminary studies indicate that defects in PCs induced by targeted HuR deletion or uc.173 silencing resulted in the concomitant loss of ISC activity in vivo as well as ex vivo and that HuR knockout and uc.173 inhibition also caused mitochondrial dysfunction, along with reduced levels of WNT3 and Notch ligands in PCs. Building on these exciting observations, we now propose the paradigm-shifting hypothesis that HuR and uc.173 regulate the PC/ISC niche by maintaining mitochondrial homeostasis, in turn regulating intestinal mucosal renewal and adaptation in critical surgical diseases. Two specific aims are proposed to test the hypothesis: 1) to define the exact role of the PC/ISC niche in HuR/uc.173-regulated intestinal mucosal growth under critical surgical conditions; and 2) to determine if HuR and uc.173 regulate PC/ISC niche function by modulating mitochondrial metabolism in response to critical surgical stress. Completion of these specific aims will uncover novel mechanisms underlying the pathogenesis of intestinal mucosal growth inhibition in patients with critical surgical disorders. It will also establish a fundamental basis for developing new effective therapeutics to promote gut mucosal growth/adaptation by targeting the PC/ISC niche activity via HuR and uc.173.