Eosinophils are innate immune leukocytes associated with asthma, allergies and other diseases. Despite the long recognition of eosinophilic involvement in asthma, specific, non-redundant roles for eosinophils in disease pathogenesis had been elusive. However, recent studies from several laboratories have revealed new functions of eosinophils in immunomodulation and airway remodeling, changing the classic paradigm of disease pathogenesis and reinvigorating the field with a promise of more specific therapeutic targets. Our overall goal is to identify and mechanistically define effector functions of eosinophils vital to the initiation and exacerbation of asthma. In line with this goal, this proposal builds upon our novel discovery that mature human eosinophils express fully functional Notch ligands and receptors, indicating eosinophils utilize Notch signaling pathways, both as signal-receiving """"""""target"""""""" cells and as signal- sending """"""""signaling"""""""" cells. Our preliminary data establishes our overlying hypothesis that Notch signaling underlies eosinophil functions critical to asthma. Our studies will specifically investigate two hypotheses: 1) Notch receptor activation is required in parallel with cytokine signals to achieve full and sustained activation of eosinophils in asthmatic airways;and 2) Eosinophils promote a Th2 milieu in asthma by Notch ligand-mediated juxtacrine interactions with T cells. While experimental approaches utilize predominantly human eosinophils, proposed studies also take full advantage of the manipulative benefits of mouse models. Our proposal may provide vital insights into the mechanistic basis for eosinophil functions pertinent to asthma, and by extension other inflammatory diseases of the lung involving eosinophilia, relevant to development of novel, targeted therapeutic approaches.

Public Health Relevance

Asthma is a highly prevalent and costly disease. Eosinophils, innate immune leukocytes associated with asthma, allergies and other diseases, are the predominant cellular infiltrate in asthmatic airways. This proposal is designed to elucidate the mechanistic basis of eosinophil functions leading to asthma exacerbation. These studies may lead to the development of novel, targeted therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095699-04
Application #
8402994
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2010-01-18
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$400,554
Indirect Cost
$164,934
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Weller, Peter F; Spencer, Lisa A (2017) Functions of tissue-resident eosinophils. Nat Rev Immunol 17:746-760
Smith, Kalmia M; Rahman, Raiann S; Spencer, Lisa A (2016) Humoral Immunity Provides Resident Intestinal Eosinophils Access to Luminal Antigen via Eosinophil-Expressed Low-Affinity Fc? Receptors. J Immunol 197:3716-3724
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Spencer, Lisa A; Bonjour, Kennedy; Melo, Rossana C N et al. (2014) Eosinophil secretion of granule-derived cytokines. Front Immunol 5:496
Ueki, Shigeharu; Melo, Rossana C N; Ghiran, Ionita et al. (2013) Eosinophil extracellular DNA trap cell death mediates lytic release of free secretion-competent eosinophil granules in humans. Blood 121:2074-83

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