Maintenance of the gut epithelial integrity under critical surgical conditions requires epithelial cells to rapidly elicit changes in gene expression patterns to regulate their survival, adapt to stress and keep epithelial homeostasis. Inhibition of mucosal growth occurs commonly in various critical surgical disorders, particularly in patients who undergo massive gastrointestinal surgical resections and are then supported with total parenteral nutrition (TPN). Because of 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, maladaptation, delayed healing, impaired barrier function, and bacterial translocation. Recently, noncoding RNAs (ncRNAs) have emerged as a novel class of master regulators of gene expression and are fundamentally involved in many biological processes and various human diseases. In preliminary studies, our genome- wide miRNA and long ncRNA (lncRNA) expression profiles reveal that fasting-induced mucosal atrophy associates with an increase in miR-195 but with a decrease in lncRNA Uc-173. Tissue-specific miR-195 deletion in intestinal epithelial cells enhances gut mucosal hyperplasia, whereas Uc-173 silencing represses mucosal growth by increasing miR-195. Based on these exciting observations, we HYPOTHESIZE that a network of miR-195/lncRNA Uc-173 interactions plays an important role in maintaining the intestinal epithelial integrity under critical surgical conditions.
Three specific aims are proposed to test the hypothesis: 1) to determine the exact role of miR-195 in gut mucosal growth and adaptation in critical surgical conditions and to further identify its targetome; 2) to determine whether lncRNA Uc-173 interacts functionally with miR-195 to jointly regulate intestinal mucosal growth and target mRNA expression in response to surgical stress; and 3) to define the mechanisms by which lncRNA Uc-173 regulates miR-195 transcription and biogenesis. Completion of these specific aims will make a significant conceptual advance by linking the miRNA/lncRNA interaction with gut mucosal regeneration and will create a fundamental base for developing novel therapies to maintain intestinal epithelial integrity in patients with critical surgical illness.

Public Health Relevance

Patients with critical surgical disorders such as trauma, thermal injury, shock, sepsis, and massive surgical operations commonly accompany with an acute inhibition of gut mucosal growth. Since the exact mechanisms underlying mucosal regeneration are still obscure, effective therapies to enhance mucosal growth and preserve the epithelial integrity in patients with critical surgical illnesses are limited, contributing to mucosal atrophy, maladaptation, delayed healing, impaired barrier function, and bacterial translocation. Completion of this project will identify novel noncoding RNAs in the regulation of gut mucosal growth and provide a fundamental base for development of new therapies to enhance mucosal renewal and adaptation 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 #
5R01DK057819-19
Application #
9957045
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Greenwel, Patricia
Project Start
2000-06-01
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
19
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Surgery
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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:
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
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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