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 美国士兵和退伍军人的死亡率和发病率。肠屏障功能障碍的作用 在创伤后并发症(如败血症)的发生中起重要作用 为毒素、过敏原和细菌移位提供主要场所 发行量。尽管肠道功能障碍在糖尿病发病机制中的重要性已得到公认 创伤后并发症，严重烧伤后的肠道通透性反应，一种主要形式 创伤的特征尚未得到很好的描述，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的机制。 热损伤时的内脏渗漏。需要检验的假设是，热损伤导致 肠道组织中的炎症激活了肠上皮细胞中的粘着斑激酶(FAK)活性， 刺激灶性重塑和上皮连接解离，从而损害肠道 上皮屏障完整性。这项提议有两个具体的目标：1)描述 FAK介导的肠屏障功能障碍及其治疗潜力 2)探讨FAK介导肠道损伤的分子机制 上皮屏障功能障碍。这项研究设计采用了免费的体内、体外和体内 将分子和遗传学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 建立新的肠道上皮屏障功能调控的分子机制。数据 从这个项目衍生出来的将会加深我们对病理生理机制的理解。 参与肠道上皮屏障功能。更重要的是，它将扩大我们对 胃肠道病理生物学，并有助于开发有效的治疗和 创伤或炎症性疾病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.