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BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

基本信息

批准号：
10693575
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 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693575
关键词：
Achievement Acute Acute Lung Injury Acute Respiratory Distress Syndrome Adherens Junction Aging American American soldier Animal Model Area Atherosclerosis Award Bacteria Bacterial Translocation Basement membrane Blood Blood Circulation Blood Vessels Cells Chairperson Chemical Burns Chronic Clinical Collaborations Communities Complex Critical Care Cultured Cells Development Diabetes Mellitus Disease Disseminated Malignant Neoplasm Dissociation Endothelium Epithelial Attachment Epithelium Evaluation Extravasation Failure Focal Adhesion Kinase 1 Focal Adhesions Functional disorder Funding Goals Hospital Charges Human Impairment Infection Inflammation Inflammatory Inflammatory Bowel Diseases Injury Intercellular Junctions Intervention Intestinal permeability Intestines Leaky Gut Length of Stay Life Literature Lung Lymph Mediating Mediator Medical Medicine Mesentery Molecular Molecular Target Morbidity - disease rate Multiple Organ Failure Obesity Operative Surgical Procedures Organ Pathogenesis Pathology Pathway interactions Patients Phase Physicians Physiological Plasma Play Population Property Pulmonary Edema Reporting Research Research Design Research Personnel Research Project Grants Role Scientist Sepsis Services Signal Transduction Site Structure Syndrome Testing Therapeutic Tight Junctions Tissues Toxin Trauma United States National Institutes of Health Vascular Diseases Veterans Work adipose derived stem cell career chronic wound clinical risk clinically relevant combat effective therapy exosome experimental study gastrointestinal gastrointestinal epithelium genetic approach heat injury high risk improved in vitro Model in vivo intestinal barrier intestinal epithelium lung injury military veteran mortality novel programs release factor response restenosis severe burns stem cell exosomes systemic inflammatory response treatment effect vascular inflammation wound care wound healing wound injury wound treatment

项目摘要

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.

项目摘要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，细菌易位肠漏是创伤时肠道屏障受损的结果，有效治疗。肠漏的病理学尚未完全表征，其细胞和分子机制仍不完全清楚。本申请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期间导致肠漏的特定机制。我们假设热损伤诱导的肠道组织炎症激活了粘着斑肠上皮中的通路导致上皮连接分离，因此，肠上皮屏障完整性。该项目将集中在1）分析分子机制， FAK介导的肠上皮屏障功能障碍; 2）评估FAK激活和 FAK抑制的治疗潜力; 3）鉴定和表征肠产生的循环器渗漏导致肺损伤的因素。研究设计采用了体内、离体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，有助于胃肠道病理学的进步，但也有临床在开发针对肠道屏障的有效疗法或外科干预中的意义损伤此外，这笔资金将支持PI参与VA服务和与VA医生和科学家合作。