Acute gut mucosal injury occurs commonly in various critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations. Since the exact mechanisms underlying mucosal injury and repair are still obscure, effective therapies to preserve the epithelial integrity in patients with critical surgical illnesses are limited, contributing to acute mucosal injury, delayed healing, impaired barrier function, and bacterial translocation. During previous funding period, we have established that the transcription factor c-myc and other growth-related proteins play an important role in epithelial cell renewal during mucosal healing and have identified a novel mechanism through which polyamines modulate c-myc expression in critical surgical conditions. However, the upsteam signaling initiating c-myc transcription after injury and how polyamines are implicated in c-myc expression remain unclear and are the focus of this competitive renewal application. Our preliminary results indicate that a) Wnt signaling is activated after mucosal injury, which exhibits a similar pattern of c-myc expression;b) knockdown of Wnt receptors represses epithelial repair;and c) polyamines modulate RNA-binding proteins TIAR and HuR that are involved in translational control of their target mRNAs. Based on these observations, we HYPOTHESIZE that 1) Wnt signaling plays a key role in mucosal healing by stimulating c-myc transcription and 2) increased polyamines following injury regulate c-myc mRNA translation by altering TIAR and HuR.
Three specific aims are proposed to test the hypotheses. 1) To determine the exact role of Wnt signaling in c-myc expression and mucosal healing after injury. 2) To define the mechanism by which Wnt activation enhances c-myc transcription during mucosal healing. 3) To investigate the mechanism by which polyamines regulate c-myc translation during healing. Completion of these specific aims will identify the up stream signals initiating c-myc transcription after mucosal injury and also yield a novel model in which c-myc mRNA translation is regulated by polyamines during healing. It is hoped that our findings will identify factors and mechanisms that can be used to preserve epithelial integrity and enhance mucosal healing in patients with critical surgical illnesses. Project Narrative: Acute gut mucosal injury occurs commonly during various critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations. Since the exact mechanisms underlying mucosal injury and repair are still obscure, effective therapies to preserve the epithelial integrity in patients with critical surgical illnesses are limited, contributing to acute mucosal injury, delayed healing, impaired barrier function, and bacterial translocation. Completion of this project will identify the molecular mechanism underlying mucosal injury and repair in critical surgical conditions and provide a fundamental base for development of new therapies to protect the gut mucosa and enhance healing in patients with critical surgical illnesses.
|Xiao, Lan; Rao, Jaladanki N; Cao, Shan et al. (2016) Long noncoding RNA SPRY4-IT1 regulates intestinal epithelial barrier function by modulating the expression levels of tight junction proteins. Mol Biol Cell 27:617-26|
|Phatak, P; Byrnes, K A; Mansour, D et al. (2016) Overexpression of miR-214-3p in esophageal squamous cancer cells enhances sensitivity to cisplatin by targeting survivin directly and indirectly through CUG-BP1. Oncogene 35:2087-97|
|Zou, Tongtong; Jaladanki, Suraj K; Liu, Lan et al. (2016) H19 Long Noncoding RNA Regulates Intestinal Epithelial Barrier Function via MicroRNA 675 by Interacting with RNA-Binding Protein HuR. Mol Cell Biol 36:1332-41|
|Hansraj, Natasha Z; Xiao, Lan; Wu, Jing et al. (2016) Posttranscriptional regulation of 14-3-3Î¶ by RNA-binding protein HuR modulating intestinal epithelial restitution after wounding. Physiol Rep 4:|
|Wang, Jun-Yao; Xiao, Lan; Wang, Jian-Ying (2016) Posttranscriptional regulation of intestinal epithelial integrity by noncoding RNAs. Wiley Interdiscip Rev RNA :|
|Gu, Hui; Yu, Jingwen; Dong, Daoyin et al. (2016) High Glucose-Repressed CITED2 Expression Through miR-200b Triggers the Unfolded Protein Response and Endoplasmic Reticulum Stress. Diabetes 65:149-63|
|Byrnes, Kimberly A; Phatak, Pornima; Mansour, Daniel et al. (2016) Overexpression of miR-199a-5p decreases esophageal cancer cell proliferation through repression of mitogen-activated protein kinase kinase kinase-11 (MAP3K11). Oncotarget 7:8756-70|
|Chung, Hee Kyoung; Chen, Yu; Rao, Jaladanki N et al. (2015) Transgenic Expression of miR-222 Disrupts Intestinal Epithelial Regeneration by Targeting Multiple Genes Including Frizzled-7. Mol Med :|
|Gu, Hui; Yu, Jingwen; Dong, Daoying et al. (2015) The miR-322-TRAF3 circuit mediates the pro-apoptotic effect of high glucose on neural stem cells. Toxicol Sci 144:186-96|
|Wang, Fang; Weng, Hongbo; Quon, Michael J et al. (2015) Dominant negative FADD dissipates the proapoptotic signalosome of the unfolded protein response in diabetic embryopathy. Am J Physiol Endocrinol Metab 309:E861-73|
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