Mechanisms of Eosinophil Effector Functions in the Lung

描述(由申请人提供)： 基因转移技术和小鼠作为人类呼吸道疾病模型的使用恰如其分地总结了候选人James(Jamie)Lee博士的研究计划。这项工作构成了候选人近期职业目标的基础，即扩大他的实验室的广度，包括对与生理相关的病理学终点越来越复杂的评估。这些眼前目标的实现反过来又支持长期目标，包括(I)将实验室的方向从分子生物学角度转向生理学计划，以及(Ii)扩大梅奥基金会，特别是亚利桑那州梅奥诊所内的老鼠研究教育活动，并包括亚利桑那州立大学的地区性研究生课程。梅奥诊所提供的机构支持和对研究和研究生教育的承诺，以及不断扩大的当地大学生物医学研究研究生课程，代表着创建一个合作中心的独特机会，该中心将鼠标作为人类疾病研究的模式系统。这一职业发展计划的一个重要目标是，利用实验室研究活动的成功，招募和培训有积极性的学生和研究员。该研究计划的目标是确定嗜酸性粒细胞和嗜酸性粒细胞效应器功能在介导变态反应性炎症中的作用(S)，从而确定它们在肺部病理发展中的作用。该方案利用了独特的嗜酸性粒细胞特异性试剂和我们在嗜酸性粒细胞生物学研究中创造的新型转基因和基因敲除小鼠。这些目标将通过完成下列目标来实现：(1)明确地确定嗜酸性粒细胞在由JJL-5和Eoaxin-2共表达产生的转基因哮喘模型中对肺病理的贡献(S)；(2)确定在IL-5/eoaxin-2转基因哮喘模型中嗜酸性粒细胞的作用机制；(3)确定嗜酸性粒细胞脱颗粒和颗粒蛋白的释放是否是嗜酸性粒细胞参与IL-5/eoaxin-2转基因哮喘模型中发生的病理的一种机制。

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.