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, but effective therapies to preserve the epithelial integrity are limited to date. Disrupton 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. Early rapid epithelial restitution is an important primary repair modality in the gut mucosa and plays a critical role in maintaining mucosal integrity, but the exact mechanism underlying this process remains unclear. Epithelial restitution occurs as a consequence of cell migration over the damaged area after superficial injury, a process that is independent of cell proliferation. Our previous studies have demonstrated that small GTPases are crucial for normal gut mucosal restitution after acute injury. However, the exact signals initiating the activation of GTPases aftr injury remain elusive and are the focus of this renewal application. a4 is a novel PP2A associated protein and is involved in many aspects of cell functions including cell motility. Our preliminary results indicate that a) early rapid mucosal restitution following injury was associate with an induction in a4 expression in mice; b) ectopic overexpression of the a4 gene enhanced epithelial restitution after wounding, whereas a4 silencing or inhibition of its downstream target -PIX repressed mucosal repair through a process involving the GTPase Rac1; and c) polyamines are necessary for normal expression of a4. Based on these exciting preliminary observations, we HYPOTHESIZE that a4 stimulates intestinal epithelial restitution after acute mucosal injury by altering PP2A/-PIX-mediated Rac1 signaling.
Three specific aims are proposed to test the hypothesis: 1) to determine the pattern and role of a4 in gut epithelial restitution after acute mucosal injury in critical surgical conditions; 2) to analyze the mechanism by which a4 regulates IEC migration during epithelial restitution; and 3) to define the cellular signaling pathways regulating a4 expression after mucosal injury, with a particular focus on cellular polyamines. Completion of this study will create a fundamental base for development of new therapies to enhance early rapid mucosal repair and preserve gut epithelial integrity under critical surgical conditions.

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 the epithelial integrity are limited to date. Delayed mucosal repair causes disruption of mucosal epithelial integrity, thus contributing to the morbidity and mortality. Although mucosal restitution is critical for maintaining epithelial integrity during criical surgical stress, the exact mechanism underlying this process remains unclear. Goal of this study is to define the cellular and molecular mechanism by which damaged mucosa is rapidly repaired by testing a novel hypothesis that a4, an important PP2A associated protein, plays a role in the regulation of gut mucosal restitution. Completion of this study will provide a fundamental base for development of new therapies to protect the gut mucosa in critical surgical illnesses and facilitate repair of damaged mucosa in our Veteran patients.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000713-06
Application #
9486833
Study Section
Surgery (SURG)
Project Start
2010-10-01
Project End
2019-09-30
Budget Start
2017-10-01
Budget End
2018-09-30
Support Year
6
Fiscal Year
2018
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:
Xiao, Lan; Rao, Jaladanki N; Cao, Shan et al. (2016) Long noncoding RNA SPRY4-IT1 regulates intestinal epithelial barrier function by modulating the expression levels of tight junction proteins. Mol Biol Cell 27:617-26

Showing the most recent 10 out of 18 publications