Wednesday, February 5, 2025 2/5/2025

Genetic and Epigenetic Programming of Allergic Airway Inflammation

Award Number: R01AI065617
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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It is appreciated that the high prevalence of asthma over the last decades reflects the interaction of susceptibility genes in affected individuals with environmental and social changes ushered by modernity [1]. A key feature of asthma is chronic airway inflammation driven and/or exacerbated by ongoing exposure to allergens and pollutants, most notably ambient particulate matter (PMs). The persistence of such inflammation suggests the derailment of normative countervailing immune regulatory mechanisms that would otherwise limit its scope. In that regard, we have identified Notch4 expression in lung regulatory T (TR) cells as a key mechanism that disrupts lung tissue homeostatic immune regulation to promote allergic airway inflammation. Notch4 is upregulated by IL-6 signaling in TR cells to activate downstream intermediates including the Wnt and Hippo pathways to promote airway Th2 and Th17 immune responses, respectively. Notch4 expression is augmented by PM, which act to induce the expression of the Notch receptor ligand Jag1 in alveolar macrophages as well as the production of IL-6. Finally, Notch4 is also upregulated on lung TR cells in the context of viral infections, thus providing a potential link between viral infections and exacerbation of allergic airway inflammation. Accordingly, our central hypothesis is that Notch4 signaling in TR cells integrates cues by allergens, pollutants and viruses to license tissue allergic inflammation. To address this hypothesis, we propose under Aim 1 to investigate the mechanisms by which Notch4 subverts TR cell function to promote allergic airway inflammation. We will investigate the role of the Notch4-activated Hippo pathway in TR cell destabilization, leading to the generation of tissue resident ex-TR cells that promote airway inflammation. We will also investigate the role of the Wnt pathway downstream of Notch4 in driving Th2 pathology, as well as the interaction of Notch4 with environmental inputs such as PMs of different sources and physiochemical properties to promote airway inflammation. We further propose under Aim 2 to investigate the role of Growth and Differentiation Factor 15 (GDF15) as a cytokine produced by lung TR cells in a Notch4-Wnt pathway-dependent manner that may contribute to tissue inflammation and pathology by acting via its receptor GFRAL on ILC2 to drive their activation and expansion. The relationship between TR cell Notch4, GDF15, IL-6 and BMI will be explored in a cohort of asthmatic subjects. Finally, under Aim 3 we will examine the role of TR cell-intrinsic viral sensing pathways alone and in synergy with Notch4 in promoting virus and allergen-induced inflammation. Our studies will help elucidate novel mechanisms fundamental to the biology of allergic airway inflammation and its augmentation by pollutants, obesity and viral infections.


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 = $653,364 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	24	12/30/2024	NON-COMPETING CONTINUATION	$653,364
														Subtotal = $653,364

Issue Date FY: 2024 ( Subtotal = $677,996 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	23	5/24/2024	NON-COMPETING CONTINUATION	$67,799
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	23	1/12/2024	NON-COMPETING CONTINUATION	$610,197
2024	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	003	22	7/25/2024	COMPETING CONTINUATION	$101,797
2024	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	21	7/25/2024	NON-COMPETING CONTINUATION	-$101,797
														Subtotal = $677,996

Issue Date FY: 2023 ( Subtotal = $703,440 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	22	2/9/2023	COMPETING CONTINUATION	$703,440
2023	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	21	2/9/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $703,440

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	20	5/6/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $594,383 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	21	8/26/2021	NON-COMPETING CONTINUATION	$594,383
														Subtotal = $594,383

Issue Date FY: 2020 ( Subtotal = $834,508 )
2020	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	20	7/21/2020	NON-COMPETING CONTINUATION	$598,508
2020	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	19	6/12/2020	SUPPLEMENT FOR EXPANSION	$127,625
2020	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	19	8/7/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	003	20	8/11/2020	SUPPLEMENT FOR EXPANSION	$108,375
														Subtotal = $834,508

Issue Date FY: 2019 ( Subtotal = $598,508 )
2019	2019	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	19	8/1/2019	NON-COMPETING CONTINUATION	$598,508
														Subtotal = $598,508

Issue Date FY: 2018 ( Subtotal = $598,508 )
2018	2018	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	003	18	8/2/2018	NON-COMPETING CONTINUATION	$598,508
2018	2016	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	16	2/27/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
2018	2016	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	16	1/17/2018	EXTENSION WITH OR WITHOUT FUNDS	$451
2018	2015	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	15	1/17/2018	NON-COMPETING CONTINUATION	-$451
														Subtotal = $598,508

Issue Date FY: 2017 ( Subtotal = $617,758 )
2017	2017	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	17	9/25/2017	COMPETING CONTINUATION	$617,758
2017	2016	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	16	9/25/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $617,758

Issue Date FY: 2016 ( Subtotal = $617,580 )
2016	2016	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	16	11/18/2015	EXTENSION WITH OR WITHOUT FUNDS	$617,580
														Subtotal = $617,580

Issue Date FY: 2015 ( Subtotal = $618,598 )
2015	2015	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	15	11/5/2014	NON-COMPETING CONTINUATION	$618,598
														Subtotal = $618,598

Issue Date FY: 2014 ( Subtotal = $619,514 )
2014	2014	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	14	6/5/2014	NON-COMPETING CONTINUATION	$61,952
2014	2014	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	14	11/14/2013	NON-COMPETING CONTINUATION	$557,562
														Subtotal = $619,514

Issue Date FY: 2013 ( Subtotal = $583,209 )
2013	2013	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	13	12/6/2012	NON-COMPETING CONTINUATION	$558,390
2013	2013	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	13	6/7/2013	NON-COMPETING CONTINUATION	$24,819
2013	2012	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	12	12/6/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $583,209

Issue Date FY: 2012 ( Subtotal = $655,883 )
2012	2012	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	004	12	7/20/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$33,435
2012	2012	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	002	11	4/9/2012	COMPETING CONTINUATION	-$471,397
2012	2012	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	003	12	4/10/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$622,448
2012	2012	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	11	11/29/2011	COMPETING CONTINUATION	$471,397
2012	2010	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	10	11/29/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $655,883

Issue Date FY: 2011 ( Subtotal = $0 )
2011	2010	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	10	2/23/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $345,663 )
2010	2010	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	10	1/15/2010	NON-COMPETING CONTINUATION	$345,663
														Subtotal = $345,663

Grand Total All Awards = $10,256,011

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Genetic and Epigenetic Programming of Allergic Airway Inflammation

Award Number: R01AI065617

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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