Mechanisms of Eosinophil Effector Functions in the Lung

描述（由申请人提供）： 使用基因转移技术和小鼠作为人类呼吸道疾病的模型恰当地总结了候选人James（Jamie）Lee博士的研究计划。这项工作构成了候选人的直接职业目标的基础，即扩大他的实验室的广度，以包括对病理学的生理相关终点的日益复杂的评估。这些近期目标的实现，反过来，支持长期目标，包括（i）从分子生物学的角度，以生理学为基础的计划，并（ii）在马约基金会，特别是马约诊所亚利桑那州内扩大小鼠研究的教育活动，并包括在亚利桑那州州立大学的区域研究生课程。马约诊所对研究和研究生教育的机构支持和承诺，以及不断扩大的当地大学生物医学研究生课程，代表了独特的机会，可以利用小鼠作为人类疾病研究的模型系统，创建一个集中努力的合作中心。这一职业发展计划的一个关键目标是招聘和培养积极的学生和研究员，利用实验室的研究活动的成功。研究提案的目标是确定嗜酸性粒细胞和嗜酸性粒细胞效应器功能介导过敏性炎症的作用，因此，它们在肺部病理学发展中的作用。该提案利用了我们在嗜酸性粒细胞生物学研究中创建的独特的嗜酸性粒细胞特异性试剂和新型转基因和基因敲除小鼠。本研究的目的是通过完成以下目标来实现的：（1）明确确定嗜酸性粒细胞对由JJL-5和eotaxin-2共表达产生的哮喘转基因模型中出现的肺部病理的贡献;（2）确定嗜酸性粒细胞效应器功能对IL-5/eotaxin-2哮喘转基因模型中出现的肺部病理负责的机制;（3）确定脱颗粒和颗粒蛋白的释放是否代表嗜酸性粒细胞促成哮喘的IL-5/eotaxin-2转基因模型中出现的病理的机制。

DESCRIPTION (provided by applicant): The use of gene transfer technologies and the mouse as a model of human respiratory diseases aptly summarizes the research program of the candidate, James (Jamie) Lee, Ph.D. This work forms the basis of the candidate's immediate career goals of expanding the breadth of his laboratory to include increasingly complex assessments of physiologically relevant endpoints of pathology. The achievement of these immediate goals, in turn, support the long term goals, including (i) To move the orientation of the lab from a molecular biology perspective to a physiology-based program and (ii) To expand the educational activities in mouse research within the Mayo Foundation, and Mayo Clinic Arizona in particular, and to include the regional graduate program at Arizona State University. The institutional support and commitment to research and graduate education offered by Mayo Clinic, together with the expanding local university graduate programs in biomedical research, represent unique opportunities to create a collaborative center of focused efforts using the mouse as a model system of human disease research. A critical objective of this career development plan is to recruit and train motivated students and fellows, capitalizing on the success of the laboratory's research activities. The goals of the research proposal are to define the role(s) of eosinophils and eosinophil effector functions mediating allergic inflammation and, therefore, their roles in the development of pulmonary pathologies. The proposal exploits unique eosinophil specific reagents and novel transgenic and gene knockout mice we have created in our studies of eosinophil biology. The objectives will be achieved through the completion of the following aims: (1) To determine unequivocally the contribution(s) of eosinophils to the pulmonary pathologies arising in a transgenic model of asthma generated by the co-expression of JJL-5 and eotaxin-2; (2) To define mechanisms of eosinophil effector functions responsible for the pulmonary pathologies occurring in the IL-5/eotaxin-2 transgenic model of asthma; (3) To determine if degranulation and the release of granule proteins represents a mechanism by which eosinophils contribute to the pathologies arising in the IL-5/eotaxin-2 transgenic model of asthma.