Molecular Control of Gut Permeability in Trauma

项目摘要 与创伤相关的全身性炎症和多器官衰竭是创伤后应激障碍的主要原因。 美国士兵和退伍军人的死亡率和发病率。肠屏障功能障碍 在创伤后并发症如败血症的发展中起重要作用， 提供毒素、过敏原和细菌移位到 流通尽管公认的重要性，肠道功能障碍的发病机制， 创伤后并发症，肠通透性反应严重烧伤，一个主要形式 创伤，尚未得到很好的表征，其细胞和分子机制， 没有被完全理解。本研究的目的是阐明细胞特异性机制， 热损伤时肠漏待检验的假设是热损伤诱导的 肠组织中的炎症激活肠上皮中的粘着斑激酶（FAK）活性， 刺激局部重塑和上皮连接分离，因此损害肠道 上皮屏障完整性。本提案提出了两个具体目标： FAK介导的肠屏障功能障碍及其治疗潜力 探讨FAK介导肠道炎症反应的分子机制 上皮屏障功能障碍研究设计采用了体内、离体和体内补充的方法。 将分子和遗传方法结合到生理实验中的体外模型 在临床相关的创伤条件下。这项研究的意义在于它有可能 建立一种新的肠上皮屏障功能调节的分子机制。数据 从这个项目中获得的信息将增强我们对病理生理机制的理解 参与肠上皮屏障功能。更重要的是，它将扩大我们对 胃肠道病理学，并有助于开发有效的治疗方法， 创伤或炎症患者肠屏障损伤的外科干预 疾病

Project Summary Systemic inflammation and multiple organ failure associated with trauma are a major cause of mortality and morbidity in American soldiers and veterans. Intestinal barrier dysfunction plays an important role in the development of posttraumatic complications such as sepsis by providing the major site for diffusion of toxins, allergens and bacterial translocation to the circulation. Despite the well- recognized importance of gut dysfunction in the pathogenesis of posttraumatic complications, the intestinal permeability response to severe burns, a major form of trauma, has not been well characterized, and its cellular and molecular mechanisms have not been fully understood. The goal of this study is to elucidate the cell-specific mechanisms of leaky guts during thermal injury. The hypothesis to be tested is that thermal injury induced inflammation in gut tissue activates focal adhesion kinase (FAK) activity in gut epithelium, stimulates focal remodeling and epithelial junction disassociation, therefore impairing gut epithelial barrier integrity. Two specific aims are developed in this proposal to: 1) characterize functional role of FAK mediated intestinal barrier dysfunction and therapeutic potential of FAK inhibition during thermal injury, and 2) explore the molecular mechanism of FAK mediated gut epithelial barrier dysfunction. The study design employs complimentary in vivo, ex vivo, and in vitro models that incorporate molecular and genetic approaches into physiological experiments under clinically relevant trauma conditions. The significance of the study lies in its potential to establish a new molecular mechanism in the regulation of gut epithelial barrier function. The data derived from this project will enhance our understanding of pathophysiological mechanisms involved in gut epithelial barrier function. More importantly, it will expand our knowledge of gastrointestinal pathobiology and contribute to the development of effective therapies and surgical interventions against gut barrier injury in patients suffered from trauma or inflammatory diseases.