This proposal for a collaborative Program Project Grant (PPG) focuses on mechanisms of TH2 inflammation in asthma. The unifying hypotheses are: (i) TH2 inflammation underlies the most common molecular phenotypes of asthma;(11) Epithelial cells secrete cytokines and chemokines to initiate and amplify TH2 inflammation in the airway;(ill) Innate helper type 2 (IH2) cells and CD4+T cells are key cellular targets of epithelial cytokines and chemokines and principal sources of TH2 cytokines in the airway. Project 1 will focus on the role of iH2 cells as proximal regulators of TH2 inflammation in the airway. This project proposes to characterize markers for these cells, delineate their role in allergic airway responses and collaborate with investigators in Project 3 to advance understanding of iH2 cells in human asthma. Project 2 will identify the miRNAs that regulate helper T cell functions relevant to asthma, examine miRNA expression patterns in CD4+T cells and iH2 cells in clinical samples from asthmatic patients, and characterize the mRNA targets and In vivo function of select miRNAs. Project 3 will investigate the role of Innate helper type 2 cells as cellular mediators of TH2-high asthma, determine how IL-33 amplifies TH2 inflammation in acute severe asthma, and explore how genetic variation in ST2 modulates airway TH2 inflammation in asthma. These projects will be supported by three cores, which will provide administrative support, access to high quality biospecimens from well-characterized asthmatic subjects and healthy controls, and expert biostatistical and bioinformatic support. The PPG represents a collaborative program of research that brings together mechanism-oriented clinical researchers from UCSF's Airway Clinical Research Center (ACRC) (Fahy and Woodruff) with disease-oriented basic immunologists from UCSF's Sandler Asthma Basic Research Center (SABRE) (Locksley and Ansel) Together, these investigators will work collaboratively using a variety of experimental approaches. Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma.

Public Health Relevance

Asthma is a common disease affecting patients from childhood to old age. Allergic airway inflammation characterized by T helper type 2 (TH2) inflammation is central to the cause of asthma, and better understanding of how TH2 inflammation starts and Is sustained in the airway will help guide new treatments for patients with asthma and other allergic diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL107202-01A1
Application #
8339948
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Noel, Patricia
Project Start
2012-08-15
Project End
2017-05-31
Budget Start
2012-08-15
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$2,231,082
Indirect Cost
$750,377
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Nusse, Ysbrand M; Savage, Adam K; Marangoni, Pauline et al. (2018) Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche. Nature 559:109-113
Ricardo-Gonzalez, Roberto R; Van Dyken, Steven J; Schneider, Christoph et al. (2018) Tissue signals imprint ILC2 identity with anticipatory function. Nat Immunol 19:1093-1099
Pavord, Ian D; Beasley, Richard; Agusti, Alvar et al. (2018) After asthma: redefining airways diseases. Lancet 391:350-400
Lachowicz-Scroggins, Marrah E; Gordon, Erin D; Wesolowska-Andersen, Agata et al. (2018) Cadherin-26 (CDH26) regulates airway epithelial cell cytoskeletal structure and polarity. Cell Discov 4:7
Bhakta, Nirav R; Christenson, Stephanie A; Nerella, Srilaxmi et al. (2018) IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma. Am J Respir Crit Care Med 197:313-324
Peters, Michael C; Ringel, Lando; Dyjack, Nathan et al. (2018) A Transcriptomic Method to Determine Airway Immune Dysfunction in T2-High and T2-Low Asthma. Am J Respir Crit Care Med :
Wong-McGrath, Kelly; Denlinger, Loren C; Bleecker, Eugene R et al. (2018) Internet-Based Monitoring in the Severe Asthma Research Program Identifies a Subgroup of Patients With Labile Asthma Control. Chest 153:378-386
Van Dyken, Steven J; Locksley, Richard M (2018) Chitins and chitinase activity in airway diseases. J Allergy Clin Immunol 142:364-369
Dunican, Eleanor M; Elicker, Brett M; Gierada, David S et al. (2018) Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. J Clin Invest 128:997-1009
Fassett, Marlys S; Pua, Heather H; Simpson, Laura J et al. (2018) Identification of Functionally Relevant microRNAs in the Regulation of Allergic Inflammation. Methods Mol Biol 1799:341-351

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