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Immune signaling molecules involved in promoting the pathogenesis of eosinophilic esophagitis (EoE)

Award Number: R01AI080581
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Eosinophilic esophagitis (EoE) is a chronic immune system disease. It has been identified only in the past two decades, but is now considered a major cause of esophageal disorder in both pediatric and adult population. The current proposal is the extension of our studies that provided novel findings including the role of IL-15 responsive iNKT cells, significance of IL-18 in IL-15 induced esophageal eosinophilia, the chemoattractant role of nerve cells derived neuropeptide VIP in EoE, and most importantly we reported a critical role IL-18 to transform IL-5 generated naïve eosinophils to CD274 expressed pathogenic eosinophils. The proposed extended studies will now establish the physiological role of IL-18 and VIP in eosinophils and mast cells accumulation and degranulation in and beyond the epithelial mucosa that promotes esophageal functional abnormalities including motility dysfunction in chronic EoE. The mechanisms driving the eosinophil and mast cell accumulation, activation and degranulation in the muscular mucosa is yet not fully understood. Notably, no evidence indicates that muscle or neuronal cells are the sources of eotaxin-1, -2 or -3. Even after a decade of reported highly induced eotaxin-3 and its correlation with esophageal eosinophilia, yet the direct physiological significance of eotaxin--3 is not established in EoE. Therefore, it is critical to understand the role of tissue specific IL-18 induction and the mechanisms operational in the trafficking and accumulation of IL-18 transformed pathogenic eosinophils and mast cells in and beyond the epithelial mucosa. Our reports indicates that eosinophils and mast cells accumulation promotes epithelial, subepithelial and muscular mucosa fibrosis, muscle cell hyperplasia and esophageal functional abnormalities in human EoE. Most recently, we reported that eosinophils accumulate adjacent to nerve cells and neuroendocrine cell-derived vasoactive intestinal peptide has a chemoattractant role for eosinophils similar to the eotaxin(s). In addition, most recently both in vitro and in vivo, we showed that VIP receptor antagonist restrict eosinophils motility. Therefore, our extended grant studies will test the hypotheses that IL-18 and a neuroendocrine cell-derived chemoattractant vasoactive intestinal peptide is critical for the maturation, activation, and accumulation of eosinophils and mast cells in each segment of the esophagus and are the key for the development of fibrosis associated strictures and motility dysfunction. Accordingly, we propose three specific aims to establish the mechanistic pathways involved in IL-18-driven eosinophil and mast cell maturation, activation, and degranulation in each segment of the esophageal mucosa (AIM I); tissue-specific IL-18 induction is critical in promoting EoE pathogenesis (AIM II) and lastly, establish the role of neuroendocrine cell-derived vasoactive intestinal peptide in eosinophil and mast cell accumulation and degranulation within the muscular mucosa that promote esophageal functional abnormalities including stricture development and motility dysfunction in EoE (Aim III).


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: 2023 ( Subtotal = $461,691 )
2023	2023	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	13	11/1/2022	NON-COMPETING CONTINUATION	$461,691
														Subtotal = $461,691

Issue Date FY: 2022 ( Subtotal = $461,691 )
2022	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	12	11/24/2021	NON-COMPETING CONTINUATION	$461,691
														Subtotal = $461,691

Issue Date FY: 2021 ( Subtotal = $466,178 )
2021	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	11	11/13/2020	NON-COMPETING CONTINUATION	$466,178
														Subtotal = $466,178

Issue Date FY: 2020 ( Subtotal = $455,125 )
2020	2020	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	10	12/12/2019	NON-COMPETING CONTINUATION	$455,125
														Subtotal = $455,125

Issue Date FY: 2019 ( Subtotal = $452,750 )
2019	2019	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	001	9	12/11/2018	COMPETING CONTINUATION	$452,750
2019	2017	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	002	8	9/26/2019	NON-COMPETING CONTINUATION	$0
2019	2017	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	8	12/10/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $452,750

Issue Date FY: 2017 ( Subtotal = $376,250 )
2017	2017	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	8	4/20/2017	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2016 ( Subtotal = $376,250 )
2016	2016	TULANE UNIVERSITY, SCHOOL OF MEDICINE	1430 TULANE AVENUE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	7	4/9/2016	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2015 ( Subtotal = $376,250 )
2015	2015	TULANE UNIVERSITY, SCHOOL OF MEDICINE	1430 TULANE AVENUE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	000	6	4/23/2015	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2014 ( Subtotal = $376,250 )
2014	2014	TULANE UNIVERSITY, SCHOOL OF MEDICINE	1430 TULANE AVENUE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	002	5	4/10/2014	NON-COMPETING CONTINUATION	$376,250
2014	2013	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	3	1/3/2014	COMPETING CONTINUATION	-$264,639
2014	2013	TULANE UNIVERSITY, SCHOOL OF MEDICINE	1430 TULANE AVENUE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	001	4	1/3/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$264,639
														Subtotal = $376,250

Issue Date FY: 2013 ( Subtotal = $371,888 )
2013	2013	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	3	4/25/2013	COMPETING CONTINUATION	$353,250
2013	2013	TULANE UNIVERSITY, SCHOOL OF MEDICINE	1430 TULANE AVENUE	NEW ORLEANS	LA	70118	ORLEANS	USA	Allergy and Infectious Diseases Research	004	4	1/3/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$264,639
2013	2013	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	3	7/19/2013	COMPETING CONTINUATION	$15,700
2013	2013	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	003	3	1/3/2014	COMPETING CONTINUATION	-$264,639
2013	2013	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	002	3	7/25/2013	COMPETING CONTINUATION	$2,938
														Subtotal = $371,888

Issue Date FY: 2010 ( Subtotal = $371,814 )
2010	2010	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Trans-NIH Recovery Act Research Support	000	2	6/7/2010	NON-COMPETING CONTINUATION	$371,814
														Subtotal = $371,814

Issue Date FY: 2009 ( Subtotal = $371,814 )
2009	2009	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Trans-NIH Recovery Act Research Support	000	1	7/17/2009	NEW	$371,814
														Subtotal = $371,814

Grand Total All Awards = $4,917,951

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Immune signaling molecules involved in promoting the pathogenesis of eosinophilic esophagitis (EoE)

Award Number: R01AI080581

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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