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

肠粘膜损伤的调节

• 批准号: 7751463
• 负责人: DAVID J HACKAM
• 金额: $ 25.76万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751463
• 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; Molecular Biology; 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

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/失血性休克后肠粘膜损伤和修复的调节。 PI：大卫J. Hackam，医学博士，哲学博士 当前提案的长期目标是定义导致发展的机制 创伤/失血性休克后肠粘膜损伤，并开发新的治疗策略， 在损伤发生后恢复肠粘膜的完整性。 创伤/失血性休克是儿童和成人发病率和死亡率的主要原因，部分原因是 全身性脓毒症和多系统器官损伤（MSOF）的发展， 伤害发生了。创伤后导致MSOF的机制仍不完全清楚， 已经显示，肠屏障的破坏与肠细菌的移位在其 发展我们现在假设，受损宿主先天免疫系统的激活 肠粘膜屏障，以及减少先天免疫系统激活策略将维持 创伤后的屏障完整性为了验证这一假设，我们提出了以下目标： 目标1。为了确定肠细胞先天性免疫受体Toll样受体4（TLR 4）和Toll样受体4（TLR 4）在肠上皮细胞中的作用， TLR 9在创伤/失血性休克后肠粘膜损伤发病机制中的作用 目标2.为了评估CpG-DNA激活TLR 9在限制肠上皮细胞中TLR 4信号传导中的作用， 对IRAK-M信号传导的影响 目标3.探讨CpG-DNA激活TLR 9对肠粘膜损伤的保护作用 在创伤/失血性休克后 我们将寻求解决这些目标，使用各种细胞生物学和生理学技术， 培养的细胞，原代肠上皮细胞和几种小鼠品系，包括我们拥有的小鼠品系， 用先天免疫受体信号传导或表达中的突变进行工程化。 相关性（参见说明）： 目前的建议与公共卫生有关，因为我们正在努力尽量减少 创伤后的发病率和死亡率，这是目前儿童死亡和残疾的主要原因 和年轻人。