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：
8970720
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/8970720
关键词：
Address Animal Model Animals Award Bacteria Bacterial Infections Bacterial Pneumonia Biological 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 Health Host Defense Human Hypersensitivity Immune Immune response Immunity In Vitro Infection Inflammatory Influenza Interleukins 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 Process Production Protein Chemistry Proteins Publications Pulmonary Inflammation 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 receptor receptor binding 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（应用程序提供）：此应用，IL-22受体的细胞调节及其在肺部免疫学中的重要性，由ME，匹兹堡医学系肺部过敏疗法部的Nathaniel Weathington，MD博士Nathaniel Weathington博士提交，并为指导的职业发展奖（K08）。我对肺部感染生物学的研究具有强烈的背景和承诺，并渴望最终指导肺部感染生物学中心。我提出了一项研究密集型职业发展的时期，并将动手和教学培训整合到计划的活动中。为了完成我的主要研究目的，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。我提供了有关白介素（IL）-22信号轴调节的初步数据，该数据对于17型免疫反应是必不可少的且受保护的。 IL-22受体（IL-22R）蛋白水平的分子调节尚不清楚，我表明IL-22R被泛素（UB）蛋白降解，并鉴定出用于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在肺上皮细胞中穿梭IL-22R蛋白降解。此外，多功能激酶糖原合酶激酶3磷酸化并稳定细胞中的IL-22R。基于此，我建议更具体地表征IL-22R调节，研究人类标本中涉及蛋白的抽象以进行疾病相关性，并检验以下假设：体内IL-22R的稳定性可以保护肺炎。我的工作将在我的主要心理和研究顾问的密切建议下进行。我还建议选择丰富转化科学和个性化医学的课程。在我的顾问，导师，部门和部门的匹兹堡大学拥有持久的支持环境，并将在2014年夏季完成我的奖学金后晋升为医学助理教授。在K08导致职业发展奖的支持下，该项目将产生出版物和演讲，我将获得我的研究，从而将我的研究开发为独立的项目，以授予独立和应用程序，以获得独立和应用程序，并在五年中获得了五年的项目。