Early mucosal restitution is an important primary repair modality in the gastrointestinal (GI) tract and its defective regulation underlies various critical pathological states such as mucosal bleeding and acute injury, disruption of GI epithelial integrity, and barrier dysfunction. Since the exact mechanisms underlying acute mucosal injury and early rapid mucosal reepithelialization after superficial wounds are still obscure, effective therapies to preserve GI epithelial integrity in clinic are limited, especially in patients with critical surgical illnesses. During previous funding period, we have established the importance of canonical transient receptor potential-1 (TRPC1)-mediated Ca2+ signaling in regulating intestinal epithelial restitution after mucosal injury. However, the exact upstream signals initiating TRPC1 channel activation after mucosal injury remain elusive and are the focus of this competitive renewal application. Recently, stromal interaction molecule 1 (STIM1) was identified in screens for molecules that are essential for the activation of store-operated Ca2+ channels (SOCs), whereas inhibition of STIM1 expression reduces store-operated Ca2+ entry (SOCE) after store depletion. Our preliminary results indicate that a) levels of levels of STIM1 at the plasma membrane increase significantly after wounding, b) overexpression of the constitutively active STIM1 EF-hand mutant increases SOCE and enhances epithelial restitution after wounding, and c) STIM1 silencing decreases SOCE and represses epithelial restitution in cells overexpressing TRPC1. Based on these exciting observations, we HYPOTHESIZE that STIM1 plays an important role in promoting GI epithelial restitution after mucosal injury by activating TRPC1 channel activity.
Three specific aims are proposed to test the hypothesis. 1) To determine the pattern and role of STIM1 in gut epithelial restitution after mucosal injury in vitro as well as in vivo. 2) To characterize functional and physical interactions of STIM1 with TRPC1 in regulating SOCE during intestinal epithelial restitution. 3) To define the cellular signaling pathways regulating STIM1 subcellular redistribution and its expression after mucosal injury. Completion of these aims will identify the up stream signals initially activating TRPC1 channels after mucosal injury and also yield a novel model in which STIM1 subcellular trafficking and expression are regulated during restitution. It is hoped that our findings will provide supportive data to strengthen our long-term goal that is to develop therapeutic approaches for GI mucosal injury-related diseases and for maintaining epithelial integrity under various clinical conditions.

Public Health Relevance

Project Narrative Immediate goal of the current study is to define the mechanisms underlying acute gut mucosal injury and repair. Various acute GI mucosal injury and gastritis are much more common at our VA patients than those observed in the general public. It has been reported that there are 24.7% prevalence of GI ulcers and injury in veteran population, compared with 10.5% in the control population. Furthermore, drugs, specifically NSAIDs, and stress as etiologic factors in GI mucosal injury and ulcerations are becoming increasing important. This is especially relevant to the new and young OEF/OIF veterans who return with a major increase in the prevalence of stress-related disorders. The incidence of stress-induced mucosal injury and ulceration in critically ill intensive patients as well as in military combat situations further aggravate the problem of GI mucosal injury and injury-related disorders in the VA population. However, the effective therapies for preventing acute gut mucosal injury and for promoting mucosal repair in clinic are limited to date, because of lacking knowledge of the mechanisms involved in gut mucosal injury and repair. Thus, improving the understanding of the processes that maintain the integrity of the gut mucosa and enhance repair is the first step towards therapeutic initiatives in this area and is the focus of the current proposal. Based on our previous studies and exciting preliminary results, studies proposed here are to determine whether a novel protein STIM1 plays an important role in promoting GI epithelial restitution after mucosal injury by Ca2+-signaling. Completion of these aims will provide supportive data to strengthen our long-term goal that is to develop therapeutic approaches for GI mucosal injury-related diseases for our VA patients.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000332-02
Application #
7784487
Study Section
Gastroenterology (GAST)
Project Start
2009-04-01
Project End
2013-09-30
Budget Start
2010-04-01
Budget End
2011-09-30
Support Year
2
Fiscal Year
2011
Total Cost
Indirect Cost
Name
Baltimore VA Medical Center
Department
Type
DUNS #
796532609
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Lai, Keane K Y; Kweon, Soo-Mi; Chi, Feng et al. (2017) Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor Development in Mice via a Wnt Positive-Signaling Loop by Stabilization of Low-Density Lipoprotein-Receptor-Related Proteins 5 and 6. Gastroenterology 152:1477-1491
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:
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
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:
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
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
Gu, Hui; Yu, Jingwen; Dong, Daoyin et al. (2016) High Glucose-Repressed CITED2 Expression Through miR-200b Triggers the Unfolded Protein Response and Endoplasmic Reticulum Stress. Diabetes 65:149-63
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
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:
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

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