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.
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.
|Mohapatra, A; Van Dyken, S J; Schneider, C et al. (2016) Group 2 innate lymphoid cells utilize the IRF4-IL-9 module to coordinate epithelial cell maintenance of lung homeostasis. Mucosal Immunol 9:275-86|
|Gordon, Erin D; Locksley, Richard M; Fahy, John V (2016) Cross-Talk between Epithelial Cells and Type 2 Immune Signaling. The Role of IL-25. Am J Respir Crit Care Med 193:935-6|
|von Moltke, Jakob; Ji, Ming; Liang, Hong-Erh et al. (2016) Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529:221-5|
|Fahy, John V (2016) Asthma Was Talking, But We Weren't Listening. Missed or Ignored Signals That Have Slowed Treatment Progress. Ann Am Thorac Soc 13 Suppl 1:S78-82|
|Pua, Heather H; Steiner, David F; Patel, Sana et al. (2016) MicroRNAs 24 and 27 Suppress Allergic Inflammation and Target a Network of Regulators of T Helper 2 Cell-Associated Cytokine Production. Immunity 44:821-32|
|Wesolowska-Andersen, Agata; Seibold, Max A (2016) Is the Road to Precision Medicine in Chronic Lung Disease Paved with Degraded Chitin? Am J Respir Crit Care Med 193:107-8|
|Gordon, Erin D; Simpson, Laura J; Rios, Cydney L et al. (2016) Alternative splicing of interleukin-33 and type 2 inflammation in asthma. Proc Natl Acad Sci U S A 113:8765-70|
|Gordon, Erin D; Palandra, Joe; Wesolowska-Andersen, Agata et al. (2016) IL1RL1 asthma risk variants regulate airway type 2 inflammation. JCI Insight 1:e87871|
|Reber, Laurent L; Fahy, John V (2016) Mast cells in asthma: biomarker and therapeutic target. Eur Respir J 47:1040-2|
|Ramstein, Joris; Broos, Caroline E; Simpson, Laura J et al. (2016) IFN-Î³-Producing T-Helper 17.1 Cells Are Increased in Sarcoidosis and Are More Prevalent than T-Helper Type 1 Cells. Am J Respir Crit Care Med 193:1281-91|
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