BLRD Research Career Scientist Award Application

项目摘要 创伤引起的炎症和多器官衰竭是死亡和 美国士兵和退伍军人的发病率。肠道屏障功能障碍在肠梗阻中起着关键作用 创伤后并发症的发展通过提供血浆泄漏的主要部位和 细菌易位。肠道渗漏，是创伤过程中肠道屏障受损的结果，目前还没有 治疗有效。肠漏的病理尚未完全定性，其细胞和 分子机制仍不完全清楚。此应用程序的总体目标是 将我目前的项目扩展到一个新的阶段，进一步研究细胞的分子控制 在创伤和随后的急性肺损伤中导致肠漏的特定机制。 我们假设热损伤引起的肠道组织炎症激活了灶性粘连。 肠上皮中导致上皮连接解离的通路，因此，损害 肠道上皮屏障完整性。本项目将主要集中在1)分子机制的分析。 FAK介导的肠上皮屏障功能障碍；2)评估FAK的激活和作用 FAK抑制剂的治疗潜力；3)确定和表征渗漏的肠源性循环器 导致肺损伤的因素。研究设计采用了免费的体内、体外和 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。这项研究的意义不仅在于它的潜力 为促进胃肠道病理生物学的进步做出贡献，也为临床做出贡献 针对肠道屏障的有效治疗或外科干预措施的开发的意义 受伤。此外，这笔资金将支持PI参与退伍军人事务部的工作和 与退伍军人管理局医生和科学家合作。

Project Summary Trauma-induced inflammation and multiple organ failure are major causes of mortality and morbidity in American soldiers and veterans. Gut barrier dysfunction plays a critical role in the development of posttraumatic complications by providing the major site for plasma leakage and bacterial translocation. Leaky gut, a consequence of gut barrier damage during trauma, has not been treated effectively. The pathology of leaky gut has not been fully characterized and its cellular and molecular mechanisms remain incompletely understood. The overall objective of this application is to expand my current project towards a new phase to further investigate the molecular control of cell specific mechanisms that contribute to leaky gut during trauma and subsequent acute lung injury. We hypothesize that thermal injury induced inflammation in gut tissue activates focal adhesion pathways in intestinal epithelium resulting in epithelial junction disassociation, therefore, impairing gut epithelial barrier integrity. The project will focus on 1) to analyze the molecular mechanism of FAK mediated gut epithelial barrier dysfunction; 2) to evaluate the role of FAK activation and therapeutic potential of FAK inhibition; 3) to identify and characterize leaky gut-produced circulator factors that contribute to lung injury. 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 not only to contribute to the advancement of gastrointestinal pathobiology, but also to have clinical implications in the development of effective therapies or surgical interventions against gut barrier injury. In addition, the funding will support PI’s effort to participate in the VA services and the collaboration with VA physicians and scientists.