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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061972-10
Application #
8231424
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Hamilton, Frank A
Project Start
2002-07-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2012
Total Cost
$294,030
Indirect Cost
$98,010
Name
University of Maryland Baltimore
Department
Surgery
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Rathor, Navneeta; Chung, Hee Kyoung; Wang, Shelley R et al. (2018) ?-PIX plays an important role in regulation of intestinal epithelial restitution by interacting with GIT1 and Rac1 after wounding. Am J Physiol Gastrointest Liver Physiol 314:G399-G407
Chung, Hee Kyoung; Wang, Shelley R; Xiao, Lan et al. (2018) ?4 Coordinates Small Intestinal Epithelium Homeostasis by Regulating Stability of HuR. Mol Cell Biol 38:
Xiao, Lan; Wu, Jing; Wang, Jun-Yao et al. (2018) Long Noncoding RNA uc.173 Promotes Renewal of the Intestinal Mucosa by Inducing Degradation of MicroRNA 195. Gastroenterology 154:599-611
Wang, Jun-Yao; Cui, Yu-Hong; Xiao, Lan et al. (2018) Regulation of Intestinal Epithelial Barrier Function by Long Noncoding RNA uc.173 through Interaction with MicroRNA 29b. Mol Cell Biol 38:
Lai, Keane K Y; Kweon, Soo-Mi; Chi, Feng et al. (2017) Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor Development in Mice via a Wnt Positive-Signaling Loop by Stabilization of Low-Density Lipoprotein-Receptor-Related Proteins 5 and 6. Gastroenterology 152:1477-1491
Wang, Peng-Yuan; Wang, Shelley R; Xiao, Lan et al. (2017) c-Jun enhances intestinal epithelial restitution after wounding by increasing phospholipase C-?1 transcription. Am J Physiol Cell Physiol 312:C367-C375
Wang, Jun-Yao; Xiao, Lan; Wang, Jian-Ying (2017) Posttranscriptional regulation of intestinal epithelial integrity by noncoding RNAs. Wiley Interdiscip Rev RNA 8:
Zhang, Yuan; Zhang, Yun; Xiao, Lan et al. (2017) Cooperative Repression of Insulin-Like Growth Factor Type 2 Receptor Translation by MicroRNA 195 and RNA-Binding Protein CUGBP1. Mol Cell Biol 37:
Liu, Lan; Zhuang, Ran; Xiao, Lan et al. (2017) HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation. Mol Cell Biol 37:
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

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