BLRD Research Career Scientist Award Application

此应用程序的总体目标是将我当前的项目扩展到一个新的阶段， 进一步研究有助于疾病的细胞特异性机制的分子控制 在美国退伍军人中很常见未来的研究重点是粘着斑的作用 在创伤期间肠屏障损伤的调节中的FAK。还将作出更多努力， 与VA外科医生合作，检查内皮屏障的分子机制 功能障碍和MMP失调导致VA患者血管重塑失败。 创伤引起的炎症和多器官衰竭是死亡的主要原因， 美国士兵和退伍军人的发病率。肠道屏障功能障碍在消化道疾病中起着关键作用。 通过提供血浆泄漏的主要部位而发展创伤后并发症， 细菌易位烧伤是一种主要的创伤形式， 没有很好的临床特征。此外，其细胞和分子机制仍然存在 不完全理解。应用的主要目标是阐明细胞特异性机制 肠漏的症状我们推测，热损伤引起的炎症反应， 组织激活肠上皮中的Src和FAK活性，刺激局部重塑和ZO 1 介导的连接分离，因此损害肠上皮屏障完整性。的具体目标 本研究的主要内容是：1）探讨FAK介导肠上皮细胞凋亡的分子机制 屏障功能障碍，和2）评估FAK激活的功能作用和治疗潜力 FAK抑制在热损伤期间肠屏障功能障碍中的作用。研究设计采用 互补的体内、离体和体外模型， 在临床相关创伤条件下进行生理实验的方法。的 这项研究的意义在于它有可能建立一个新的分子途径， 紧密连接和粘附连接。从研究工作中收集的信息不仅有助于 胃肠道病理生物学的进步，但也有临床意义， 针对VA中肠屏障损伤的有效疗法或外科干预的开发 创伤和炎症性肠病患者。

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 the diseases that are commonly in American Veterans. The future research focuses on the role of focal adhesion kinase (FAK) in the regulation of gut barrier injury during trauma. Additional efforts will be devoted in collaboration with VA surgeons to examining molecular mechanisms of endothelial barrier dysfunction and MMP dysregulation that lead to the failure of vascular remodeling in VA patients. 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. The intestinal epithelial barrier damage in burns, a major form of trauma, has not been well characterized clinically. In addition, its cellular and molecular mechanisms remain incompletely understood. The major goal of application is to elucidate the cell-specific mechanisms of leaky guts during thermal injury. We hypothesize that thermal injury induced inflammation in gut tissue activates Src and FAK activity in intestinal epithelium, stimulate focal remodeling and ZO1 mediated junction disassociation therefore impairing gut epithelial barrier integrity. The specific goals developed in this study are: 1) to analyze the molecular mechanism of FAK mediated gut epithelial barrier dysfunction, and 2) to evaluate the functional role of FAK activation and therapeutic potential of FAK inhibition in gut barrier dysfunction during thermal 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 to establish a new molecular pathway in the regulation of tight and adherens junctions. Information gleaned from the research work will not only contribute to the advancement of gastrointestinal pathobiology, but also has clinical implications in the development of effective therapies or surgical interventions against gut barrier injury in the VA patients with trauma and inflammatory bowel diseases.