Inhibition of intestinal mucosal growth occurs commonly in various critical surgical disorders such as trauma, shock, and massive surgical operations. Because our deficient understanding of the mechanism underlying this critical pathological process, effective therapies to maintain the mucosal epithelial integrity in patients with critical surgical illnesses are limited, leading to mucosal atrophy, delayed healing, impaired barrier function, and bacterial translocation. Recently, the essential contribution of posttranscriptional events, particularly altered mRNA turnover and translation, in the control of gene expression program in the GI mucosa is becoming increasingly recognized, but little is known about their importance in the pathogenesis of mucosal growth inhibition in critical surgical conditions. Based on our significant progress during the previous funding period and exciting preliminary studies, experiments proposed in this competitive renewal application are to test the HYPOTHESIS that the RNA-binding protein CUGBP1 plays an important role in the regulation of intestinal mucosal growth by altering expression of its target mRNAs encoding growth-regulatory proteins and its effect is regulated by given microRNAs and cellular polyamines.
Three specific aims are proposed to test the hypothesis. 1) To determine the exact role of CUGBP1 in the regulation of gut mucosal growth in critical surgical conditions and to further identify its target mRNAs. 2) To determine whether microRNAs and CUGBP1 jointly regulate the stability and translation of target mRNAs in response to surgical stress. 3) To define the mechanisms by which polyamines regulate CUGBP1 expression and microRNA biogenesis. Completion of these specific aims will uncover novel functions of CUGBP1 and microRNAs in the pathogenesis of gut mucosal growth inhibition and will impact upon efforts to improve therapeutical approaches for patients suffering gut mucosal atrophy. It is hoped that these studies will identify potential therapeutic targets and agents which could be used in the future to maintain intestinal mucosal integrity in patients with critical surgical illnesses.

Public Health Relevance

Acute gut mucosal growth inhibition occurs commonly in various critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations. Since the exact mechanisms underlying mucosal growth inhibition are still obscure, effective therapies to preserve the epithelial integrity in patients with critical surgical illnesses are limited, contributing to mucosal atrophy, delayed healing, impaired barrier function, and bacterial translocation. Completion of this project will identify the molecular mechanism underlying this critical pathological process in critical surgical conditions and provide a fundamental base for development of new therapies to enhance mucosal epithelial renewal 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 #
5R01DK057819-12
Application #
8290441
Study Section
Special Emphasis Panel (ZRG1-SBIB-Q (02))
Program Officer
Carrington, Jill L
Project Start
2000-06-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
12
Fiscal Year
2012
Total Cost
$274,050
Indirect Cost
$56,550
Name
University of Maryland Baltimore
Department
Surgery
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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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:
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:
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 14-3-3? by RNA-binding protein HuR modulating intestinal epithelial restitution after wounding. Physiol Rep 4:
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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