Acute gut barrier dysfunction occurs commonly in patients with critical surgical disorders such as trauma, burns, sepsis, hemorrhage, and massive surgical operations, leading to the translocation of luminal toxic substances and bacteria to the blood stream. Since the exact mechanism underlying the acute barrier dysfunction remains largely unknown, effective therapies to protect the barrier integrity and enhance its functional recovery are limited, contributing to death in critically surgical patients with leaky gut. Recentl, long noncoding RNAs (lncRNAs) have emerged as a novel class of master regulators of gene expression and are fundamentally involved in many biological processes and different human diseases. The goal of this competitive renewal application is to determine the functions of lncRNAs H19 and SPRY4-IT1 in the control of tight junction (TJ) expression and gut permeability under critical surgical conditions by carrying out a series of multi-disciplinary studies. Our preliminary results indicate that a) target deletion of H19 in mice protects the TJ barrier function under surgical conditions, whereas H19 overexpression represses TJ protein expression and increases paracellular permeability; b) lncRNA SPRY4-IT1 silencing destabilizes TJ mRNAs and thus increases epithelial paracellular permeability; SPRY4-IT1 binding to TJ mRNAs requires the RNA-binding protein HuR; and c) decreasing cellular polyamines increases lncRNA H19 levels but decreases lncRNA SPRY4-IT1. Based on these exciting observations, we HYPOTHESIZE that lncRNAs H19 and SPRY4-IT1 play an important role in the regulation of TJ expression and gut barrier function by interacting with HuR in critica surgical conditions and their cellular abundances are regulated by polyamines.
Three specific aims are proposed to test the hypothesis: 1) to define the exact roles of lncRNAs H19 and SPRY4-IT1 in the regulation of TJ expression and barrier function during critical surgical stress; 2) to characterize the interactions between HuR and lncRNAs H19 and SPRY4-IT1 in the regulation of TJ protein expression in response to surgical stress; and 3) to determine if polyamines function as novel regulators of expression of lncRNAs H19 and SPRY4-IT1. Completion of these specific aims will make a significant conceptual advance by linking the lncRNA-mediated TJ expression with gut permeability in patients with critical surgical illness and will create a fundamental base for development of novel and more effective therapies to preserve the epithelial barrier integrity.
Acute gut barrier dysfunction occurs commonly in various critical surgical disorders such as trauma, thermal injury, shock, and massive surgical operations. Since the exact mechanism underlying gut barrier dysfunction is still obscure, effective therapies to preserve the integrity of the epithelial barrier in patients with critical surgical illnesses are limited, contributing to translocation of luminal bacteria/toxin to the bloo stream, sepsis, multiple organ dysfunction syndrome, and death. Completion of this project will identify the pathogenesis of acute gut barrier dysfunction in critical surgical conditions and provide a fundamental base for development of new therapies to protect the intestinal mucosa and maintain the integrity of the epithelial barrier in patients with severe surgical diseases.
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