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 illnesss are limited, contributing to mucosal hemorrhage, delayed healing, epithelial barrier dysfunction, and the translocation of luminal toxic substances and bacteria to the blood stream. During previous funding period, we have demonstrated that activation of Wnt signaling stimulates mucosal healing after acute injury and also identified a novel mechanism through which the RNA-binding proteins HuR and AUF1 regulate expression of c-Myc and JunD in critical surgical conditions. Recently, the essential contribution of posttranscriptional events, particularly altere mRNA turnover and translation through microRNAs (miRNAs), in the control of gene expression program in the mucosal tissues is becoming increasingly recognized, but little is known about their importance in the control of mucosal injury/repair 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 miRNA-222 (miR-222) and miR-503 play an important role in the regulation of mucosal healing after acute injury in critical surgical conditions by altering the stability and/or translation of arget mRNAs.
Three specific aims are proposed to test the hypothesis. 1) To define the exact roles of miR-222 and miR-503 in mucosal healing after acute injury in critical surgical conditions. 2) To determine if miR-222 and miR-503 regulate mucosal healing by altering the stability and translation of their target mRNAs. 3) To characterize the exact mechanism by which miR-222 and miR-503 regulate expression of key molecules of Wnt signals under surgical stress. Completion of these specific aims will make a significant conceptual advance by linking the miRNA- mediated posttranscriptional regulation with mucosal healing in patients with critical surgical illness and will create a fundamental base for development of novel therapies to preserve the epithelial integrity. Moreover, the identification of the mRNA targets that mediate the actions of miRNAs in mucosal healing will also reveal previously unrecognized components of cellular stress responses that may serve as targets for more traditional drug development.

Public Health Relevance

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 illnesss are limited, contributing to acute mucosal hemorrhage, 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)
Type
Research Project (R01)
Project #
2R01DK061972-11A1
Application #
8694328
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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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
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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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