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，Nathaniel Weathington博士，医学博士，匹兹堡大学医学系肺过敏和重症监护医学部提交，以获得指导职业发展奖（K 08）。我有很强的背景和承诺，在肺部炎症生物学的研究与愿望，最终直接对肺部炎症生物学中心。我建议在职业发展的研究密集期，将实践和教学培训纳入计划的活动。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。我目前的初步数据调制的白细胞介素（IL）-22信号轴，这是必不可少的和保护17型免疫反应。IL-22受体（IL-22 R）蛋白水平的分子调控是未知的，我表明，IL-22 R是由泛素（Ub）蛋白酶体降解与IL-22 R泛素化的分子基序的鉴定。我还观察到未表征的Ub E3连接酶亚基FBXW 22穿梭于IL-22 R蛋白在肺上皮细胞中降解。此外，多功能激酶糖原合酶激酶3使细胞中的IL-22 R磷酸化并稳定化。基于此，我建议更具体地描述IL-22 R调节，研究人类样本中相关蛋白的丰度以用于疾病相关性，并测试IL-22 R在体内的稳定性可以防止肺炎的假设。我的工作将在我的主要导师和研究顾问的密切配合下进行。我还建议选择课程的丰富转化科学和个性化医学。我有一个持久的支持在匹兹堡大学的环境，从我的顾问，导师，司和部门，并将晋升为医学助理教授在我的奖学金在2014年夏天完成。在K 08指导职业发展奖的支持下，该项目将产生出版物和演示文稿，我将把我的研究发展为一个独立的项目，并在未来五年内过渡到独立和申请R 01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.