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
Ouyang, Miao; Su, Weijie; Xiao, Lan et al. (2015) Modulation by miR-29b of intestinal epithelium homoeostasis through the repression of menin translation. Biochem J 465:315-23
Liu, Lan; Christodoulou-Vafeiadou, Eleni; Rao, Jaladanki N et al. (2014) RNA-binding protein HuR promotes growth of small intestinal mucosa by activating the Wnt signaling pathway. Mol Biol Cell 25:3308-18
Chung, Hee Kyoung; Rao, Jaladanki N; Zou, Tongtong et al. (2014) Jnk2 deletion disrupts intestinal mucosal homeostasis and maturation by differentially modulating RNA-binding proteins HuR and CUGBP1. Am J Physiol Cell Physiol 306:C1167-75
Xiao, Lan; Wang, Jian-Ying (2014) RNA-binding proteins and microRNAs in gastrointestinal epithelial homeostasis and diseases. Curr Opin Pharmacol 19:46-53
Rathor, Navneeta; Zhuang, Ran; Wang, Jian-Ying et al. (2014) Src-mediated caveolin-1 phosphorylation regulates intestinal epithelial restitution by altering Ca(2+) influx after wounding. Am J Physiol Gastrointest Liver Physiol 306:G650-8
Cao, Shan; Xiao, Lan; Rao, Jaladanki N et al. (2014) Inhibition of Smurf2 translation by miR-322/503 modulates TGF-?/Smad2 signaling and intestinal epithelial homeostasis. Mol Biol Cell 25:1234-43
Yu, Ting-Xi; Rao, Jaladanki N; Zou, Tongtong et al. (2013) Competitive binding of CUGBP1 and HuR to occludin mRNA controls its translation and modulates epithelial barrier function. Mol Biol Cell 24:85-99
Xiao, Lan; Rao, Jaladanki N; Zou, Tongtong et al. (2013) miR-29b represses intestinal mucosal growth by inhibiting translation of cyclin-dependent kinase 2. Mol Biol Cell 24:3038-46
Zhuang, Ran; Rao, Jaladanki N; Zou, Tongtong et al. (2013) miR-195 competes with HuR to modulate stim1 mRNA stability and regulate cell migration. Nucleic Acids Res 41:7905-19
Liu, Lan; Rao, Jaladanki N; Zou, Tongtong et al. (2012) Activation of Wnt3a signaling stimulates intestinal epithelial repair by promoting c-Myc-regulated gene expression. Am J Physiol Cell Physiol 302:C277-85

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