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Regulation of Intestinal Mucosal Injury & Repair After Trauma/Hemorrhagic Shock

肠粘膜损伤的调节

基本信息

批准号：
8103247
负责人：
DAVID J HACKAM
金额：
$ 26.24万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8103247
关键词：
Acute Address Adult Apoptosis Attenuated Bacterial Translocation Biological Cause of Death Cells Cessation of life Child Development Disease Doctor of Philosophy Engineering Enterobacteriaceae Enterocytes Failure Figs - dietary Goals Healed Hemorrhage Hemorrhagic Shock Homologous Gene IRAK3 gene Immune Immune system Immunologic Receptors In Vitro Injury Instruction Intestines Lead Ligands Modeling Morbidity - disease rate Mouse Strains Mutant Strains Mice Mutation Organ failure Pathogenesis Pathway interactions Physiological Play Primary Cell Cultures Receptor Activation Receptor Signaling Regulation Role Sepsis Signal Transduction System TLR9 gene Techniques Testing Time Trauma Up-Regulation body system healing in vivo inhibitor/antagonist injured injury and repair mortality novel therapeutics public health relevance receptor repaired toll-like receptor 4 young adult

项目摘要

Regulation of Intestinal Mucosal Injury and Repair after Trauma/Hemorrhagic shock. PI: David J. Hackam, MD, PhD The long-term goal of the current proposal is to define the mechanisms that lead to the development of intestinal mucosal injury after trauma/hemorrhagic shock, and to develop novel therapeutic strategies to restore intestinal mucosal integrity after injury has occurred. Trauma/hemorrhagic shock is a leading cause of morbidity and mortality in children and adults, in part due to the development of systemic sepsis and multi-system organ injury (MSOF) several days after the initial injury has occurred. The mechanisms that lead to MSOF after trauma remain incompletely understood, yet a breakdown of the intestinal barrier with translocation of enteric bacteria has been shown to play a role in its development. We now hypothesize that activation of the innate immune system of the injured host damages the intestinal mucosal barrier, and that strategies that reduce innate immune system activation will maintain barrier integrity after trauma. To test this hypothesis, we propose the following aims: Aim 1. To determine the role of enterocyte innate immune receptors Toll like receptor 4 (TLR4) and Toll like Receptor 9 (TLR9) in the pathogenesis of intestinal mucosal injury after trauma/hemorrhagic shock. Aim 2. To assess the role of TLR9 activation with CpG-DNA in limiting TLR4 signaling in enterocytes via effects on IRAK-M signaling Aim 3. To determine the role of TLR9 activation with CpG-DNA in protecting against intestinal mucosal injury after trauma/hemorrhagic shock. We will seek to address these aims using a variety of cell biological and physiological techniques using cultured cells, primary enterocytes and in several strains of mice, including mice strains that we have engineered with mutations in innate immune receptor signaling or expression. RELEVANCE (See instructions): The public health relevance of the current proposal lies in the fact that we are seeking to minimze the morbidity and mortality after trauma, which is currently the leading cause of death and disablity in children and young adults.

创伤/失血性休克后肠黏膜损伤的调控与修复。