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.

Public Health Relevance

This K08 Career Development Award application is submitted by Dr. Nathaniel M. Weathington of the University of Pittsburgh Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine. The project described herein addresses the regulation of an important receptor (the interleukin-22 rceptor) on cells of the lung to protect against bacterial infections and pneumonia. We propose to carry this work forward through the study of specific mechanistic details of this receptor's normal and abnormal processing. We will also evaluate if and how levels of this receptor are different in patients with different diseases, and determine if increasing the amounts of this receptor present in the lungs of mice protects them against pneumonia.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1)
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Caler, Elisabet V
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Weathington, Nathaniel M; Álvarez, Diana; Sembrat, John et al. (2018) Ex vivo lung perfusion as a human platform for preclinical small molecule testing. JCI Insight 3:
Wang, Dan; Zhao, Jing; Li, Shuang et al. (2018) Phosphorylated E2F1 is stabilized by nuclear USP11 to drive Peg10 gene expression and activate lung epithelial cells. J Mol Cell Biol 10:60-73
Weathington, Nathaniel M; Kanth, Shreya M; Gong, Qiaoke et al. (2017) IL-4 Induces IL17Rb Gene Transcription in Monocytic Cells with Coordinate Autocrine IL-25 Signaling. Am J Respir Cell Mol Biol 57:346-354
Lendermon, Elizabeth A; Coon, Tiffany A; Bednash, Joseph S et al. (2017) Azithromycin decreases NALP3 mRNA stability in monocytes to limit inflammasome-dependent inflammation. Respir Res 18:131
Gaggar, Amit; Weathington, Nathaniel (2016) Bioactive extracellular matrix fragments in lung health and disease. J Clin Invest 126:3176-84
Franz, Joseph; Jerome, Jacob; Lear, Travis et al. (2015) The Human IL-22 Receptor Is Regulated through the Action of the Novel E3 Ligase Subunit FBXW12, Which Functions as an Epithelial Growth Suppressor. J Immunol Res 2015:912713