Patients with critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations are commonly complicated with acute gut mucosal injury and bleeding. Disruption of the gut epithelial integrity causes sepsis and in some instances acts as the trigger that drives multiple organ dysfunction syndrome (MODS), a leading cause of death in critically ill patients. Effective therapies to enhance mucosal defense and promote epithelial repair after acute injury in patients with critical surgical illnesses are limited, contributing to massive mucosal hemorrhage, impaired repair, and gut barrier dysfunction. During the previous funding periods, we have demonstrated that protein phosphatase 2A (PP2A)-associated protein ?4 plays an important role in intestinal mucosal regeneration and defense, but its exact mechanism underlying ?4-regulated intestinal homeostasis remains largely unknown. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long ncRNAs (lncRNAs), have recently emerged as a novel class of master regulators of the intestinal epithelium homeostasis and are also implicated in different human diseases. miRNAs and lncRNAs modulate expression of target genes and thus regulate a variety of cellular processes. Our preliminary results indicate that a) targeted deletion of ?4 in mice decreased the levels of mucosal miR-503 and lncRNA uc.230 in the intestine; b) specific inhibition of miR-503 and uc.230 by transfection with their antagonisms repressed intestinal epithelial repair after wounding and also enhanced epithelial cell apoptosis; and c) miR-503 inhibited expression of antizyme (AZ; a negative regulator of polyamine biosynthesis), whereas uc.230 up-regulated Rac1 and inhibitor of apoptosis protein 1 (IAP1). Based on these exciting observations, we HYPOTHESIZE that ?4 promotes intestinal epithelial homeostasis by modulating miRNA miR- 503 and lncRNA uc.230 in critical surgical conditions.
Three specific aims are proposed to test the hypothesis: 1) to examine the expression profiles of miRNAs and lncRNAs in the ?4-deficient intestinal epithelium in response to surgical stress; 2) to determine the exact roles of miR-503 and uc.230 in ?4-regulated mucosal repair and apoptosis; and 3) to define the mechanisms by which miR-503 and uc.230 regulate expression of AZ, Rac1, and IAP1. Completion of these specific aims will make a conceptual advance by linking ?4/ncRNA pathway with gut epithelium homeostasis under critical surgical conditions. These studies will also create a fundamental basis for development of novel therapies to preserve epithelial integrity in our VA patients, thus decreasing morbidity and mortality of massive mucosal injury and inflammation, delayed repair, sepsis, and MODS by targeting ?4 and its regulatory ncRNAs.

Public Health Relevance

Patients with critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations are commonly complicated with gut mucosal injury and bleeding, but effective therapies to preserve epithelial integrity are limited to date. Delayed mucosal repair causes disruption of mucosal epithelial integrity, thus contributing to morbidity and mortality. Although mucosal healing after acute injury is crucial for maintaining epithelial integrity during critical surgical stress, the exact mechanism underlying this process remains unclear. The immediate goal of this study is to define the cellular and molecular mechanisms underlying intestinal epithelium homeostasis under critical surgical conditions. We will test the possibility that an important protein ?4 controls gut mucosal homeostasis by altering given noncoding RNAs. Completion of these experiments will create a fundamental basis for development of novel therapies to preserve epithelial integrity in our VA patients.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX000713-08
Application #
9889594
Study Section
Special Emphasis Panel (ZRD1)
Project Start
2010-10-01
Project End
2024-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Baltimore VA Medical Center
Department
Type
DUNS #
796532609
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
Phatak, Pornima; Burrows, Whitney M; Chesnick, Ingrid E et al. (2018) MiR-199a-3p decreases esophageal cancer cell proliferation by targeting p21 activated kinase 4. Oncotarget 9:28391-28407
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, 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
Xu, Yan; Shen, Liangfang; Lu, Zhaoxia et al. (2017) Concomitant stromal tumor and early cancer of the stomach: What should be done? Medicine (Baltimore) 96:e7576
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:
Xu, Yan; Chen, Jie; Xiao, Lan et al. (2016) Transcriptional regulation of importin-?1 by JunD modulates subcellular localization of RNA-binding protein HuR in intestinal epithelial cells. Am J Physiol Cell Physiol 311:C874-C883

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