Chemokines in lung transplantation

描述(由申请人提供)： 有了拟议的临床科学家发展导师奖，申请者将继续他对肺部炎症基本机制的研究。在这个实验室工作了两年后，申请者仍然坚定地致力于学术肺部医学的事业。拟议的研究将使申请者掌握免疫学、细胞和分子生物学方面的广泛实验室技术。研究经验将由免疫学和医学研究计划补充。该项目的重点是肺移植后炎症和纤维化的发展以及趋化因子在这些过程中的作用。肺移植后，移植肺可能会出现几种类型的损伤，包括缺血再灌注损伤、急性排斥反应和慢性排斥反应。这些免疫介导的损伤导致了呼吸道瘢痕的形成，即所谓的闭塞性细支气管炎(BO)。超过50%的肺移植术后会发生BO，这仍然是肺移植后发病率和死亡率的主要原因。中性粒细胞是缺血再灌注损伤的重要组成部分，而T淋巴细胞是急性和慢性排斥反应的主要介质。拟议的项目将确定移植后产生哪些趋化因子，以及它们在移植物损伤和随后的BO发展中的作用。进一步的实验将操纵趋化因子或趋化因子受体在肺移植动物模型中的表达，以探讨它们在移植物损伤和BO发生中的作用。申请人特别建议：(1)研究急性排斥和BO患者移植后趋化因子和趋化因子受体的表达；(2)利用小鼠肺移植气管异位模型，研究趋化因子在呼吸道缺血再灌注损伤发生中的作用；(3)在小鼠肺移植气管异位模型中，研究趋化因子在急性呼吸道排斥反应和BO发生发展中的作用；(4)建立一种新颖的小鼠气道排斥和BO模型。

DESCRIPTION (provided by applicant): With the proposed Mentored Clinical Scientist Development Award the applicant will continue his investigations into basic mechanisms of lung inflammation. After two productive years in this laboratory the applicant remains firmly committed to a career in academic pulmonary medicine. The proposed research will allow the applicant to master a broad range of laboratory techniques in immunology, cell, and molecular biology. The research experience will be supplemented by a program of study of immunology and medical science. The project focuses on the development of inflammation and fibrosis following lung transplantation and the role of chemokines in these processes. After a lung is transplanted there may be several types of injury to the graft, including ischemia-reperfusion injury, acute rejection, and chronic rejection. These immune mediated injuries contribute to the development of scarring of the airways, so called bronchiolitis obliterans (BO). Over 50% of all lung transplants will develop BO after transplantation, and this remains the major cause of morbidity and mortality after lung transplantation. Neutrophils have been shown to be a prominent component of ischemia-reperfusion injury while T lymphocytes are the primary mediators of both acute and chronic rejection. The proposed project will determine which chemokines are produced after transplantation and their contribution to the development of graft injury and subsequent BO. Further experiments will manipulate chemokine or chemokine receptor expression in animal models of lung transplantation to investigate their role in the development of graft injury and BO. The applicant specifically proposes to: (1) investigate the expression of chemokines and chemokine receptors in the lung following transplantation in patients with and without acute rejection and BO; (2) investigate the role of chemokines in the development of ischemia-reperfusion injury in the airways using the murine tracheal heterotopic model of lung transplantation; (3) investigate the role of chemokines in the development of acute airway rejection and the development of BO in the murine tracheal heterotopic model of lung transplantation; (4) develop a novel murine model of airway rejection and BO.