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Mechanisms of IL-33 secretion in allergic diseases

Award Number: R01AI128729
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/16/2016
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Mechanisms of IL-33 secretion in allergic diseases - PROJECT SUMMARY/ABSTRACT The long-term objective of this project is to investigate the fundamental immunological mechanisms involved in the development of asthma and allergic diseases. It is becoming increasingly clear that cytokines produced by epithelial cells, including thymic stromal lymphopoietin, IL-25, and IL-33, play an important role in shaping type 2 immunity and in the pathophysiology of allergic diseases. However, major gaps remain in our knowledge concerning the molecular and cellular control of production and secretion of these cytokines. In this application, we will investigate the mechanisms involved in IL-33 secretion. IL-33 is primarily stored in the nucleus of non-hematologic cells; nuclear localization is a unique feature of this cytokine. We previously found that exposure of human airway epithelial cells to a fungal allergen, Alternaria alternata, evokes rapid extracellular release of ATP, which triggers sustained increases in intracellular calcium concentration and IL-33 secretion into the extracellular milieu. We also found that airway epithelial cells release acetylcholine (ACh) extracellularly following Alternaria or house dust mite allergen exposure. Importantly, blocking M3 muscarinc receptors (M3R) on epithelial cells suppressed ATP release and IL-33 secretion, suggesting an autocrine role for ACh. Therefore, we hypothesize that allergen-induced ACh secretion by the airway epithelium plays a pivotal role in triggering a sequence of intracellular events that lead to extracellular release of IL-33. The experiments described in this proposal will investigate key steps of this process in detail. In Aim 1, we will deterimne how airborne allergen exposure triggers ACh secretion and early cellular responses in airway epithelial cells in vitro. In Aim 2, we will investigate how epithelium-derived ACh facilitates IL-33 secretion by focusing on the autocrine ACh/M3R signaling pathway and protein kinase C-dependent phosphorylation of key regulatory proteins. In Aim 3, we will investigate the role of epithelial ACh/M3R signaling in allergen-induced IL- 33 secretion and initiation of type 2 immunity in the lung by using mouse models of allergic inflammation. We will employ a combination of complementary expertise in molecular and cell biology, pharmacology and immunology in the laboratories of Dr. O’Grady and Dr. Kita. Novel and robust in vitro and in vivo models have been developed for this project. These studies will provide a better understanding of how the epithelium responds to environmental allergens and will define key cellular and molecular mechanisms responsible for secretion of IL-33. Ultimately, these studies will characterize critical mechanism(s) involved in allergen-induced immune responses, allowing for identification of novel therapeutic target(s) to treat and ideally prevent immune-mediated airway diseases, such as asthma, chronic rhinosinusitis, and other allergic disorders.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $582,546 )
2025	2025	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Allergy and Infectious Diseases Research	000	9	2/13/2025	NON-COMPETING CONTINUATION	$582,546
														Subtotal = $582,546

Issue Date FY: 2024 ( Subtotal = $604,553 )
2024	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Allergy and Infectious Diseases Research	001	8	5/24/2024	NON-COMPETING CONTINUATION	$60,455
2024	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Allergy and Infectious Diseases Research	000	8	1/29/2024	NON-COMPETING CONTINUATION	$544,098
														Subtotal = $604,553

Issue Date FY: 2023 ( Subtotal = $609,009 )
2023	2023	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Allergy and Infectious Diseases Research	000	7	1/26/2023	NON-COMPETING CONTINUATION	$609,009
														Subtotal = $609,009

Issue Date FY: 2022 ( Subtotal = $630,120 )
2022	2022	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Allergy and Infectious Diseases Research	000	6	2/11/2022	COMPETING CONTINUATION	$630,120
2022	2021	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Allergy and Infectious Diseases Research	001	5	8/25/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $630,120

Issue Date FY: 2021 ( Subtotal = $516,518 )
2021	2021	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Allergy and Infectious Diseases Research	000	5	11/16/2020	NON-COMPETING CONTINUATION	$516,518
														Subtotal = $516,518

Issue Date FY: 2020 ( Subtotal = $521,369 )
2020	2020	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Allergy and Infectious Diseases Research	003	4	5/11/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$98,842
2020	2020	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Allergy and Infectious Diseases Research	001	4	11/29/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$521,369
2020	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	3	11/29/2019	NON-COMPETING CONTINUATION	$0
2020	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	002	3	5/11/2020	NON-COMPETING CONTINUATION	-$98,842
														Subtotal = $521,369

Issue Date FY: 2019 ( Subtotal = $510,759 )
2019	2019	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	3	11/14/2018	NON-COMPETING CONTINUATION	$510,759
														Subtotal = $510,759

Issue Date FY: 2018 ( Subtotal = $509,737 )
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	2	11/17/2017	NON-COMPETING CONTINUATION	$509,737
														Subtotal = $509,737

Issue Date FY: 2017 ( Subtotal = $522,735 )
2017	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	1	12/15/2016	NEW	$522,735
														Subtotal = $522,735

Grand Total All Awards = $5,007,346

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Mechanisms of IL-33 secretion in allergic diseases

Award Number: R01AI128729

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/16/2016

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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