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

IL-22 受体的细胞调节及其在肺免疫中的重要性。

基本信息

批准号：
9185338
负责人：
NATHANIEL M WEATHINGTON
金额：
$ 15.98万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9185338
关键词：
Address Alpha Cell Animal Model Animals Award Bacteria Bacterial Infections Bacterial Pneumonia Biological Biological Models Biology Cell membrane Cells Cessation of life Clinical Containment Critical Care Cytokine Receptors Data Disease Doctor of Philosophy Effector Cell Environment Enzymes Epithelial Epithelial Cells Epithelium Fellowship Functional disorder Gases Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Health Host Defense Human Hypersensitivity Immune Immune response Immunity In Vitro Infection Inflammatory Influenza Interleukin Receptor Irritants K-Series Research Career Programs Klebsiella pneumonia bacterium Laboratories Leukocytes Ligation Lung Lung Inflammation Lysosomes Mediating Medicine Mentors Molecular Mus Normal tissue morphology Organ Patients Phosphorylation Phosphotransferases Pneumonia Post-Translational Protein Processing Production Protein Chemistry Proteins Publications Pulmonary Inflammation Receptor Signaling Recovery Regulation Research Rest Role STAT3 gene Sampling Sepsis Signal Transduction Signaling Protein Specimen Surface System Techniques Testing Training Translational Research Translations Ubiquitin Ubiquitination Universities Work antimicrobial peptide base career development cell growth regulation cytokine immune activation in vivo interleukin-22 killings mouse model multicatalytic endopeptidase complex novel pathogen personalized medicine prevent professor protein degradation public health relevance receptor receptor binding receptor expression response ubiquitin-protein ligase

项目摘要

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.

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，匹兹堡大学医学系肺过敏科医学博士 Nathaniel Weathington 博士提交和重症监护医学指导职业发展奖（K08）我对肺部炎症生物学研究有着深厚的背景和承诺，并希望最终指导肺部炎症生物学中心的研究密集期。将实践和教学培训纳入计划的职业发展中，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。 IL)-22 信号轴对 17 型免疫反应至关重要并具有保护作用。IL-22 受体 (IL-22R) 蛋白水平的分子调节尚不清楚，我表明 IL-22R 会被泛素降解。 (Ub) 蛋白酶体，鉴定出 IL-22R 泛素化的分子基序。我还观察到，未表征的 Ub E3 连接酶亚基 FBXW22 运送 IL-22R 蛋白在肺上皮细胞中降解。 3 磷酸化并稳定细胞中的 IL-22R，我建议更具体地表征 IL-22R 调节，研究人类标本中丰富的相关蛋白质的疾病相关性，并测试体内 IL-22R 的稳定性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建议下进行，我还建议选择课程作业。我在匹兹堡大学获得了我的顾问、导师、部门和系的持久支持，并将在 2014 年夏季完成奖学金后晋升为医学助理教授。来自的支持K08 指导职业发展奖，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项目，并在未来五年内过渡到独立并申请 R01 项目奖。