BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10454207
• 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
• 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/10454207
• 关键词: 3-Dimensional; Achievement; Acute Respiratory Distress Syndrome; Adherens Junction; 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

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标是将我当前的项目扩展到一个新阶段 进一步研究导致疾病的细胞特异性机制的分子控制 这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 激酶（FAK）在调节创伤期间肠道屏障损伤中的作用。将投入额外的努力 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和死亡的主要原因 美国士兵和退伍军人的发病率。肠道屏障功能障碍在 提供血浆渗漏的主要部位，从而导致创伤后并发症的发生 细菌易位。烧伤是一种主要的创伤形式，肠上皮屏障受损 临床上尚未得到很好的表征。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 热损伤期间漏肠的情况。我们假设热损伤引起肠道炎症 组织激活肠上皮中的 Src 和 FAK 活性，刺激局部重塑和 ZO1 介导的连接解离因此损害肠上皮屏障的完整性。具体目标 本研究的进展是：1）分析FAK介导的肠上皮细胞的分子机制 屏障功能障碍，2) 评估 FAK 激活的功能作用和治疗潜力 热损伤期间肠道屏障功能障碍中 FAK 抑制的作用。研究设计采用 结合分子和遗传的互补体内、离体和体外模型 临床相关创伤条件下的生理实验方法。这 该研究的意义在于它有可能建立一条新的分子调控途径 紧密且粘附的连接。从研究工作中收集的信息不仅有助于 胃肠道病理学的进步，同时也具有临床意义 开发针对退伍军人事务部肠道屏障损伤的有效疗法或手术干预措施 患有外伤和炎症性肠病的患者。