Cellular regulation of the IL-22 receptor and its importance in lung immunity.

 描述(由申请人提供)：本申请，IL-22受体的细胞调节及其在肺免疫中的重要性，由我，博士Nathaniel Weathington，医学博士在匹兹堡大学医学系，肺过敏，重症护理医学指导职业发展奖(K08)提交。我有很强的背景，并致力于肺部炎症生物学的研究，并渴望最终领导一个肺部炎症生物学中心。我建议在职业发展的研究密集期，将实践和授课培训融入计划的活动中。为了完成我的主要研究目标，我将获得并扩展蛋白质化学、细胞生物学和动物模型技术方面的专业知识。我提供了关于白细胞介素22信号轴的调节的初步数据，这对于17型免疫反应是必要的和保护的。IL-22受体(IL-22R)蛋白水平的分子调控尚不清楚，我发现IL-22R被泛素(Ub)蛋白酶体降解，并鉴定了IL-22R泛素化的分子基序。我还观察到，未知的Ub E3连接酶亚单位FBXW22穿梭在肺上皮细胞中降解IL-22R蛋白。此外，多功能激酶糖原合成酶激酶3可磷酸化并稳定细胞内的IL-22R。基于此，我建议更具体地描述IL-22R的调节，研究人体标本中涉及的蛋白的丰度与疾病的相关性，并检验IL-22R在体内稳定可以预防肺炎的假设。我的工作将在我的主要导师和研究顾问的密切指导下进行。我还建议精选课程，以丰富翻译科学和个性化医学。我在匹兹堡大学得到了我的导师、导师、部门和部门的长期支持，并将在2014年夏天完成我的研究员职位后被提升为医学助理教授。在K08导师职业发展奖的支持下，这个项目将产生出版物和演示文稿，我将在未来五年内将我的研究发展为一个独立的项目，过渡到独立并申请R01项目奖。

 DESCRIPTION (provided by applicant): This application, Cellular regulation of the IL-22 receptor and its importance in lung immunity, is submitted by me, Dr. Nathaniel Weathington, MD PhD in the University of Pittsburgh Department of Medicine, Division of Pulmonary Allergy, and Critical Care Medicine for a mentored Career Development Award (K08). I have a strong background and commitment to research in pulmonary inflammation biology with aspirations to ultimately direct a center on lung inflammation biology. I propose a research-intensive period of career development with hands-on and didactic training integrated into the activities planned. To complete my primary research Aims, I will gain and extend expertise in protein chemistry, cell biologic, and animal model techniques. I present preliminary data on modulation of the interleukin (IL)-22 signaling axis, which is essential and protective for Type 17 immune responses. Molecular regulation of IL-22 receptor (IL-22R) protein levels is unknown, and I show that IL-22R is degraded by the ubiquitin (Ub) proteasome with identification of a molecular motif for IL-22R ubiquitination. I also observe that the uncharacterized Ub E3 ligase subunit FBXW22 shuttles the IL-22R protein for degradation in lung epithelial cells. Further, the multi-functional kinase glycogen synthase kinase 3 phosphorylates and stabilizes IL-22R in cells. Based on this, I propose to more specifically characterize IL-22R regulation, study abundance of involved proteins in human specimens for disease correlation, and test the hypothesis that stabilization of IL-22R in vivo can protect from pneumonia. My work will proceed under close advisement from my primary mentor and research advisors. I also propose select coursework for enrichment on translational science and personalized medicine. I have an environment of enduring support at the University of Pittsburgh from my advisors, mentor, division, and department, and will be promoted to Assistant Professor of Medicine on completion of my fellowship in summer 2014. With support from the K08 mentored Career Development Award, this project will yield publications and presentations, and I will develop my research to an independent project with a transition to independence and application for an R01 project award in the next five years.