NEUTROPHIL RECRUITMENT IN LPS-INDUCED AIRWAY DISEASE

描述(摘自调查人员摘要) 这项提案的总体目标包括一项促进职业发展的计划 Jessica Klekamp博士的发展，同时了解一项 内毒素介导的呼吸道损伤的基本成分--中性粒细胞 向肺部募集。克莱坎普博士的长期职业目标是发展 成为独立企业的教育、研究技能和经验 能够在生物医学领域做出有意义贡献的内科医生-科学家 科学。这一奖项将使她能够实现她的眼前目标 在分子水平上加深对细胞相互作用的理解 通过课程学习，获得分子生物学方面的新研究技能，以及 继续她对白细胞和内皮细胞黏附的研究 分子。这一职业发展计划将在理想的情况下进行 美国国立卫生研究院支持的环境呼吸道专业中心的环境 疾病，大卫·A·施瓦茨博士是她的导师，也是首席研究员 为这个专业中心。这种环境为Klekamp博士提供了 资源和充分利用科学专业知识以取得重大进展 对环境肺病研究的贡献。建议数 研究项目调查控制早期致病事件 中性粒细胞从血管间隙到呼吸道的运动 建立内毒素诱导的小鼠呼吸道疾病模型。虽然这个角色 白细胞/内皮细胞黏附分子在中性粒细胞募集中的作用 体循环已经被很好地定义，这些因素的参与 肺循环中的分子还不太清楚，它们的 在吸入性内毒素损伤中的具体作用还没有研究。整体而言 这项研究的假设是，一个局部激活的血管 内皮细胞用于将中性粒细胞从肺毛细血管中移出。 将(和支气管毛细血管后小静脉)循环至空域 在吸入内毒素之后。具体目标集中在互动上 从中性粒细胞和内皮细胞开始 血管内皮细胞激活，随后中性粒细胞激活 整合素和牢固的内皮细胞黏附，并最终在 跨内皮细胞层的轮回。这样做的目的是 调查的目的是确定在每一个过程中是否进行了干预 中性粒细胞募集的不同阶段将有效地限制炎症 应答，并预防内毒素介导的病理生理后果 呼吸道疾病。

DESCRIPTION (Taken from the Investigator's Abstract) The overall goal of this proposal includes a plan to foster the career development of Dr. Jessica Klekamp while understanding the investigation of a fundamental component of endotoxin mediated airway injury- neutrophil recruitment to the lung. Dr. Klekamp's long term career goal is to develop the education, research skills, and experience to become an independent physician-scientist capable of making a meaningful contribution in biomedical science. This award ,would allow her to fulfill her immediate goals of furthering her understanding of cellular interactions at the molecular level through course work, attaining new research skills in molecular biology, and continuing her investigation of leukocyte and endothelial cell adhesion molecules. This career development plan would take place in the ideal environment of the NIH-supported Specialized Center in Environmental Airway Disease, with Dr. David A. Schwartz as her mentor, the principal investigator for this specialized Center. This environment provides Dr. Klekamp both the resources and full access to the scientific expertise to make a significant contribution to the study of environmental lung disease. The proposed research project investigates the early pathogenic events that control movement of neutrophils from the vascular space to the airway, in an established murine model of endotoxin induced airway disease. While the role of leukocyte/endothelial cell adhesion molecules in neutrophil recruitment in the systemic circulation has been well defined, the involvement of these molecules in the pulmonary circulation is less well understood, and their specific role in inhaled LPS injury has not been studied. The overall hypothesis of this investigation is that a localized activated vascular endothelium serves to move the neutrophil from the pulmonary capillary circulation (and the bronchial post-capillary venules) to the airspace following inhalation of endotoxin. The specific aims focus on the interaction of the neutrophil and the endothelium in a stepwise fashion beginning with activation of the endothelium, followed by activation of the neutrophil integrins and firm adhesion to the endothelium, and culminating in transmigration across the endothelial cell layer. The goal of this investigation is to determine whether interventions during each of these phases of neutrophil recruitment will effectively limit the inflammatory response, and prevent the pathophysiologic consequences of endotoxin mediated airway disease.