In proposal we will investigate the role of epigenetic mechanisms in the pathogenesis of allergic asthma and rhinitis. Asthma affects 1 in 15 Americans - over 23 million people - thus making it one of the country's most common and also costly diseases. Current therapies do not cure asthma or control daily symptoms for patients with severe disease, prompting us to adopt """"""""out-of-box"""""""" approaches to find novel therapies for asthma. Our goal is to directly address the unmet need for asthma sufferers by harnessing the seminal discoveries made in the field of epigenetics to benefit asthma research. Multiple lines of evidence suggest an important role for epigenetic mechanisms in asthma. Specifically, we have identified disease-specific epigenetic signatures in the T helper 2 (TH2) cytokine locus (encompassing the 1L4, IL5 and ILI 3 genes) in patients with moderate asthma compared to patients with mild asthma or controls. In addition, we recently discovered TET proteins that convert 5-methylcytosine (5mC) to 5-hydroxymethyl-cytosine (hmC)in DNA, thus creating a completely new epigenetic mark;and have shown that Tet proteins and 5hmC are expressed in T cells. These are exciting findings because hydroxylation of 5mC alters DNA methylation status in a hitherto unprecedented way, and because DNA methylation is relevant to several fields including mammalian development, cancer, aging, cell lineage specification, genome defense, stem cell function and immunology. We propose to extend these studies to identify epigenetic signatures that correlate with asthma development and severity, by comparing histone modifications and DNA methylation/ hydroxy-methylation patterns in enriched populations of pathogenic epitope-specific T cells isolated from blood of allergic rhinitis subjects and asthmatic patients, categorized based on clinical severity into mild and moderately severe asthmafics. Our study will be the first to define disease-related epigenetic changes in patients with wellcharacterized asthma, and to correlate these with disease severity to obtain specific markers for disfinguishable disease states. We will test the hypothesis that asthma - a chronic allergic disease - is characterized by perturbations in these epigenetic processes in epitope-specific T cells, that can be recognized and read out as long-range epigenetic changes at relevant disease-associated loci.
In Aim 1, we will map histone modification patterns in T cells that initiate and maintain airway inflammafion in allergic asthma.
In Aim 2, we will profile patterns of DNA methylation and hydroxymethylation in T cells in asthma.
In Aim 3, we will identify epigenetic markers of disease by establishing and analyzing an integrated database of epigenefic, genetic, transcriptomic, funcfional and clinical data. These proposed studies are novel and innovative. They will have a broad impact on our understanding of asthma, and set an important precedent for invesfigafing the role of epigenetic mechanisms in other immune-mediated disorders. We will test the hypothesis that asthma - a chronic allergic disease - is characterized by perturbations in these epigenetic processes in epitope-specific T cells, that can be recognized and read out as long-range epigenetic changes at relevant disease-associated loci.
In Aim 1, we will map histone modification patterns in T cells that initiate and maintain airway inflammafion in allergic asthma.
In Aim 2, we will profile patterns of DNA methylation and hydroxymethylation in T cells in asthma.
In Aim 3, we will identify epigenetic markers of disease by establishing and analyzing an integrated database of epigenefic, genetic, transcriptomic, funcfional and clinical data. These proposed studies are novel and innovative. They will have a broad impact on our understanding of asthma, and set an important precedent for invesfigafing the role of epigenetic mechanisms in other immune-mediated disorders.

Public Health Relevance

Asthma can be a devastating illness for the 23 million Americans affected by this disease. The emerging field of epigenefics, which aims to define how genes are turned on and off in cells, has already shown great promise in finding new therapies for many human diseases, especially cancer. We have already identified epigenetic changes in known asthma-related genes that correlate with moderate asthma but not mild asthma. In this proposal, we will focus our analysis on cells that drive disease pathogenesis i.e. epitopespecific TH2 cells, and demonstrate comprehensively that perturbafions in the epigenefic state of T cells are observed in pafients with well-characterized asthma. Our findings should directly benefit human asthma research by identifying novel asthma-related genes that may be targets for new therapeutic drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI100275-03
Application #
8637926
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Pham, J; Oseroff, C; Hinz, D et al. (2016) Sequence conservation predicts T cell reactivity against ragweed allergens. Clin Exp Allergy 46:1194-205
Oseroff, Carla; Christensen, Lars H; Westernberg, Luise et al. (2016) Immunoproteomic analysis of house dust mite antigens reveals distinct classes of dominant T cell antigens according to function and serological reactivity. Clin Exp Allergy :
Seumois, Grégory; Zapardiel-Gonzalo, Jose; White, Brandie et al. (2016) Transcriptional Profiling of Th2 Cells Identifies Pathogenic Features Associated with Asthma. J Immunol 197:655-64
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Westernberg, Luise; Schulten, Véronique; Greenbaum, Jason A et al. (2016) T-cell epitope conservation across allergen species is a major determinant of immunogenicity. J Allergy Clin Immunol 138:571-578.e7
Hinz, D; Seumois, G; Gholami, A M et al. (2016) Lack of allergy to timothy grass pollen is not a passive phenomenon but associated with the allergen-specific modulation of immune reactivity. Clin Exp Allergy 46:705-19
Engel, Isaac; Seumois, Grégory; Chavez, Lukas et al. (2016) Innate-like functions of natural killer T cell subsets result from highly divergent gene programs. Nat Immunol 17:728-39
Oseroff, Carla; Pham, John; Frazier, April et al. (2016) Immunodominance in allergic T-cell reactivity to Japanese cedar in different geographic cohorts. Ann Allergy Asthma Immunol 117:680-689.e1
Carrasco Pro, Sebastian; Sidney, John; Paul, Sinu et al. (2015) Automatic Generation of Validated Specific Epitope Sets. J Immunol Res 2015:763461
Paul, Sinu; Lindestam Arlehamn, Cecilia S; Scriba, Thomas J et al. (2015) Development and validation of a broad scheme for prediction of HLA class II restricted T cell epitopes. J Immunol Methods 422:28-34

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