The goals of the proposed research are to determine the mechanisms that lead to the development of necrotizing enterocolitis (NEC), which is the leading cause of death and disability from gastrointestinal disease in premature infants, and to determine novel therapeutic strategies for this devastating disorder. To do so, we will explore the role of the bacterial endotoxin receptor Toll like receptor 4 (TLR4) in the pathogenesis of NEC through its previously unrecognized effects on the induction of endoplasmic reticulum (ER) stress in the intestinal mucosa of the premature infant. ER stress reflects a cellular state of accumulated mis-folded proteins within the lumen of the ER, which leads to rapid apoptosis. In the previous funding period, we discovered that TLR4 signaling in the intestinal mucosa is required for NEC development and that NEC is characterized by a TLR4-dependent induction of enterocyte apoptosis leading to mucosal injury. We also showed that the homologous receptor for TLR4, namely TLR9 - which recognizes bacterial DNA (""""""""CpG-DNA"""""""") - attenuated NEC through the inhibition of TLR4 signaling and a reduction in enterocyte apoptosis. Importantly however, the mechanisms by which TLR9 inhibited the TLR4 signaling pathways that lead to NEC remained unexplained. We now provide evidence that TLR4 activation leads to NEC through an increase in ER stress within the newborn intestinal epithelium, and that TLR9 activation protects against NEC by inhibiting TLR4- mediated ER stress via the intracellular chaperone heat shock protein 70 (Hsp70). Strikingly, the premature mouse was characterized by a TLR4-dependent increase in ER stress in the intestinal epithelium, a finding also seen in human infants. We now hypothesize that TLR4 activation within the newborn intestinal mucosa leads to the development of NEC by inducing ER stress in the intestinal epithelium leading to enterocyte apoptosis, which can be reversed by TLR9 activation through the intracellular chaperone Hsp70. We further hypothesize that the in-utero regulation of intestinal TLR4 and TLR9 in the developing fetus can reduce ER stress and prevent the development of NEC. We will test this hypothesis in three specific aims:
AIM 1. To investigate the role of TLR4 activation in regulating ER stress in the newborn intestinal epithelium in the pathogenesis of necrotizing enterocolitis.
AIM 2. To determine the mechanisms by which TLR9 activation reduces TLR4-induced ER stress and NEC severity.
AIM 3. To evaluate whether the in utero regulation of TLR4 and TLR9 can inhibit ER stress and prevent the development of NEC. These studies will make a significant conceptual advance by defining how TLR4 signaling leads to enterocyte apoptosis and mucosal injury in NEC, and by explaining the susceptibility of the premature infant to NEC based on increased TLR4-induced mucosal ER stress, and through the evaluation of novel anti-NEC therapies based upon the attenuation of ER stress within the premature small intestine.
Necrotizing enterocolitis is the leading cause of death from gastrointestinal disease in premature infants, and for which there exists no effective cure. The current proposal seeks to understand the causes of necrotizing enterocolitis by focusing on how activation of the immune system causes destruction of the lining of the intestine, and seeks to reverse this damage in order to discover novel treatments for this devastating disease.
|Cunningham, Kellie E; Vincent, Garret; Sodhi, Chhinder P et al. (2016) Peroxisome Proliferator-activated Receptor-Î³ Coactivator 1-Î± (PGC1Î±) Protects against Experimental Murine Colitis. J Biol Chem 291:10184-200|
|Jia, Hongpeng; Sodhi, Chhinder P; Yamaguchi, Yukihiro et al. (2016) Pulmonary Epithelial TLR4 Activation Leads to Lung Injury in Neonatal Necrotizing Enterocolitis. J Immunol 197:859-71|
|Egan, Charlotte E; Sodhi, Chhinder P; Good, Misty et al. (2016) Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis. J Clin Invest 126:495-508|
|Deng, Meihong; Ma, Tao; Yan, Zhengzheng et al. (2016) Toll-like Receptor 4 Signaling on Dendritic Cells Suppresses Polymorphonuclear Leukocyte CXCR2 Expression and Trafficking via Interleukin 10 During Intra-abdominal Sepsis. J Infect Dis 213:1280-8|
|Fritz, Michael; Klawonn, Anna M; Nilsson, Anna et al. (2016) Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice. J Clin Invest 126:695-705|
|Ladd, Mitchell R; NiÃ±o, Diego F; March, John C et al. (2016) Generation of an artificial intestine for the management of short bowel syndrome. Curr Opin Organ Transplant 21:178-85|
|NiÃ±o, Diego F; Sodhi, Chhinder P; Hackam, David J (2016) Necrotizing enterocolitis: new insights into pathogenesis and mechanisms. Nat Rev Gastroenterol Hepatol 13:590-600|
|Shaffiey, Shahab A; Jia, Hongpeng; Keane, Timothy et al. (2016) Intestinal stem cell growth and differentiation on a tubular scaffold with evaluation in small and large animals. Regen Med 11:45-61|
|Good, Misty; Sodhi, Chhinder P; Yamaguchi, Yukihiro et al. (2016) The human milk oligosaccharide 2'-fucosyllactose attenuates the severity of experimental necrotising enterocolitis by enhancing mesenteric perfusion in the neonatal intestine. Br J Nutr 116:1175-1187|
|Sodhi, Chhinder P; Jia, Hongpeng; Yamaguchi, Yukihiro et al. (2015) Intestinal Epithelial TLR-4 Activation Is Required for the Development of Acute Lung Injury after Trauma/Hemorrhagic Shock via the Release of HMGB1 from the Gut. J Immunol 194:4931-9|
Showing the most recent 10 out of 53 publications