INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
Principal Investigator: John V Fahy
Abstract: 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.
Funding Period: 2012-08-15 - 2017-05-31
more information: NIH RePORT
- Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and diseaseSteven J Van Dyken
Departments of Medicine and Microbiology and Immunology, Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA
Annu Rev Immunol 31:317-43. 2013....
- Asthma: NHLBI Workshop on the Primary Prevention of Chronic Lung DiseasesDaniel J Jackson
1 Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
Ann Am Thorac Soc 11:S139-45. 2014....
- Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and γδ T cellsSteven J Van Dyken
Howard Hughes Medical Institute and Departments of Medicine, Microbiology, and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA
Immunity 40:414-24. 2014....
- MicroRNA regulation of the germinal center responseDirk Baumjohann
Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143, USA Electronic address
Curr Opin Immunol 28:6-11. 2014....
- Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthmaMichael C Peters
Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, Calif Cardiovascular Research Institute, University of California, San Francisco, Calif
J Allergy Clin Immunol 133:388-94. 2014..Little is known about the utility of gene profiling in sputum as a molecular phenotyping method...
- Type 2 innate lymphoid cells control eosinophil homeostasisJesse C Nussbaum
Department of Medicine, University of California San Francisco, San Francisco, California 94143 0795, USA
Nature 502:245-8. 2013....
- Type 2 innate lymphoid cells constitutively express arginase-I in the naive and inflamed lungJennifer K Bando
1 UCSF, 513 Parnassus Ave, S 1004, San Francisco, CA 94143, USA
J Leukoc Biol 94:877-84. 2013..brasiliensis infection. Thus, ILC2s are a novel source of Arg1 in resting tissue and during allergic inflammation. ..
- MicroRNA-mediated regulation of T helper cell differentiation and plasticityDirk Baumjohann
Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, California 94143, USA
Nat Rev Immunol 13:666-78. 2013....
- The microRNA cluster miR-17∼92 promotes TFH cell differentiation and represses subset-inappropriate gene expressionDirk Baumjohann
Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, California, USA
Nat Immunol 14:840-8. 2013..Our results identify the miR-17∼92 cluster as a critical regulator of T cell-dependent antibody responses, TFH cell differentiation and the fidelity of the TFH cell gene-expression program. ..
- Regulation of miRNA biogenesis and turnover in the immune systemYelena Bronevetsky
Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA, USA
Immunol Rev 253:304-16. 2013..A better understanding of these processes and their regulation by immunogenic stimuli is critical for integrating miRNAs into current models of gene expression networks that determine cell identity and immune function...
- Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophagesAri B Molofsky
Howard Hughes Medical Institute, University of California, San Francisco, San Francisco 94143, USA
J Exp Med 210:535-49. 2013..Thus, ILC2s are resident in VAT and promote eosinophils and AAM implicated in metabolic homeostasis, and this axis is enhanced during Th2-associated immune stimulation...
- Eri1: a conserved enzyme at the crossroads of multiple RNA-processing pathwaysMolly F Thomas
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA Sandler Asthma Basic Research Center, University of California San Francisco, San Francisco, CA 94143, USA
Trends Genet 30:298-307. 2014..This emerging view highlights the possibility for crosstalk and coregulation of diverse cellular processes regulated by RNA. ..
- CHEMISTRY AND BIOLOGY OF HEPARAN SULFATEUMESH RAMANLAL DESAI; Fiscal Year: 2013..End of Abstract) ..
- CENTER FOR BIOMEDICAL RESEARCHTimothy Turner; Fiscal Year: 2013..abstract_text> ..
- Neuro-Circulatory Function in Chronic Heart FailureIrving H Zucker; Fiscal Year: 2013..The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project. ..
- Neutralizing Antibody &AAV FIX Gene TherapyRichard J Samulski; Fiscal Year: 2013..The long-term objective of this PPG is to advance basic understanding of vector-cell-animal model interactions for safe gene delivery. ..
- Rocky Mountain Regional Center of Excellence or Biodefense and Emerging InfectiouJohn T Belisle; Fiscal Year: 2013..abstract_text> ..
- INTEGRATED MECHANISMS OF CARDIAC MALADAPTATIONR John Solaro; Fiscal Year: 2013..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..
- UNMC EPPLEY CANCER CENTER SUPPORT GRANTKenneth H Cowan; Fiscal Year: 2013....
- Glycan Modulation of Inflammatory ResponsesAjit P Varki; Fiscal Year: 2013..abstract_text> ..
- Thrombus Formation and Antithrombotic InterventionJohn H Griffin; Fiscal Year: 2013..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..