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)
Type
Research Program Projects (P01)
Project #
5P01HL107202-03
Application #
8676909
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Program Officer
Noel, Patricia
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Locksley, Richard M; Fahy, John V (2014) Asthma and the flu: a tricky two-step. Immunol Cell Biol 92:389-91
Van Dyken, Steven J; Mohapatra, Alexander; Nussbaum, Jesse C et al. (2014) Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and ?? T cells. Immunity 40:414-24
Bronevetsky, Yelena; Ansel, K Mark (2013) Regulation of miRNA biogenesis and turnover in the immune system. Immunol Rev 253:304-16

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