BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

基本信息

批准号：
10265422
负责人：
MACK H WU
金额：
--
依托单位：
JAMES A. HALEY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265422
关键词：
3-Dimensional Achievement Adherens Junction Adult Respiratory Distress Syndrome Aging American American soldier Area Arteriovenous fistula Atherosclerosis Award Bacteria Bacterial Translocation Basement membrane Blood Blood Vessels Blood specimen Burn injury Cell-Cell Adhesion Cells Chemical Burns Chronic Clinical Collaborations Complex Critical Care Data Development Diabetes Mellitus Disease Disseminated Malignant Neoplasm Dissociation Endothelium Epithelial Evaluation Experimental Models Extravasation Failure Focal Adhesion Kinase 1 Focal Adhesions Functional disorder Glean Goals Hospital Charges Image Impairment Inflammation Inflammatory Inflammatory Bowel Diseases Injury Intercellular Junctions Intervention Intestinal permeability Intestines Ischemia Knockout Mice Lead Leaky Gut Length of Stay Life Literature Matrix Metalloproteinases Mediating Mediator of activation protein Medical Medicine Molecular Molecular Genetics Morbidity - disease rate Mucous Membrane Multiple Organ Failure Obesity Operative Surgical Procedures Organ Pathogenesis Pathway interactions Patients Permeability Phase Physiological Plasma Play Prognosis Property Protein Isoforms Regulation Reporting Research Research Design Research Personnel Role Scientist Sepsis Signal Transduction Site Structure Superoxide Dismutase Surgeon Syndrome Techniques Testing Therapeutic Tight Junctions Tissues Toxin Trauma Vascular Diseases Vascular remodeling Veterans Work Writing base career chronic wound clinically relevant combat effective therapy experimental study fluorescence imaging gastrointestinal gastrointestinal epithelium genetic approach heat injury improved in vitro Model in vivo insight intestinal barrier intestinal epithelium military veteran monocyte mortality novel predict clinical outcome programs response restenosis severe burns success systemic inflammatory response transcription factor wound care wound healing wound treatment

项目摘要

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.

该应用程序的总体目的是将我当前的项目扩展到一个新阶段进一步研究了导致疾病的细胞特异性机制的分子控制通常在美国退伍军人中。未来的研究重点是焦点粘附的作用激酶（FAK）调节创伤期间肠道屏障损伤。额外的努力将付诸实践与VA外科医生合作检查内皮屏障的分子机制功能障碍和MMP功能障碍导致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率和美国士兵和退伍军人的发病率。肠道障碍功能障碍在通过为血浆泄漏和细菌易位。烧伤的肠上皮屏障损伤是一种主要的创伤形式，具有在临床上没有很好地表征。另外，其细胞和分子机制仍然存在不完全理解。应用的主要目的是阐明细胞特异性机制热损伤期间肠道泄漏。我们假设热损伤诱导肠道炎症组织在肠上皮中激活SRC和FAK活性，刺激局灶性重塑和ZO1 因此，介导的连接拆分会损害肠道上皮屏障完整性。具体目标在这项研究中开发的是：1）分析FAK介导的肠上皮的分子机制屏障功能障碍和2）评估FAK激活和治疗潜力的功能作用热损伤期间肠道屏障功能障碍的FAK抑制作用。研究设计采用合并分子和遗传的体内，体内和体外模型在临床相关的创伤条件下进行生理实验的方法。这该研究的重要性在于其在调节中建立新的分子途径的潜力紧密而粘附的连接。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发展，但也具有临床意义开发有效的疗法或针对VA中肠道屏障损伤的手术干预措施创伤和炎症性肠病的患者。