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Integration of Leukotriene and Prostaglandin Receptor Signaling in Mast cell Activation and Pulmonary Inflammation during Asthma

Award Number: R01AI144115
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: 02/20/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Integration of Leukotriene and Prostaglandin Receptor Signaling in Mast cell Activation and Pulmonary Inflammation during Asthma - Project Summary Mast cells (MCs) are effector cells in asthma and their activation causes secretion of cysteinyl leukotrienes (cys-LTs) and prostaglandins (PGs). MCs not only secrete these mediators, but they also possess receptors for them, to perceive their signals. Cys-LTs are potent bronchoconstrictors, powerful inducers of vascular leakage, potentiators of airway hyper-responsiveness and play an important role in asthma and other inflammatory disorders. Cys-LTs mainly act through two G-protein-coupled receptors (GPCR), CysLT1R and CysLT2R. Another GPCR, GPR17 is activated by LTD4. Both CysLT2R and GPR17 negatively regulate CysLT1R function. LTE4, the most abundant and stable of the cys-LTs, is a weak, partial agonist for the CysLT1R and CysLT2R. However, LTE4 induces unique responses in vivo that cannot be recapitulated by LTC4 or LTD4. In MC, LTE4 is more potent than LTD4 and relays signals through peroxisome proliferator activating receptor (PPAR)-γ and P2Y12R. Recently, GPR99 was identified as another CysLTR with a preference for LTE4. Understanding how all these cys-LT receptors (CysLTR) interact with each other in response to multiple ligands is critical, especially considering their role in airway physiology. Further, cys-LTs together with PGE2 synergistically potentiate calcium flux, c- Fos, COX-2, PGD2 and Macrophage Inflammatory Protein-1β (MIP-1β; CCL4)) generation in MCs. Interestingly, LTD4-PGE2 synergism is blocked only by combined treatment of CysLT1R antagonist (MK571/ singulair) and EP3 antagonist (L-798), suggesting the need for a combination of CysLT1R antagonists and EP3R antagonists to treat inflammation in asthma. LTD4+PGE2 synergism also potentiates pulmonary inflammation in der f sensitized mice (recruitment of immune cells, goblet cell metaplasia, up-regulation of inflammatory transcripts). Similar to LTD4, LTE4 synergizes with PGE2 but it differs from LTD4 via signals involving PPARγ. Based on these observations, we hypothesize that cys- LTs induce complex interactions between cys-LT-responsive receptors to profoundly influence the downstream signaling by switching anti-inflammatory PGE2 signaling to pro-inflammatory, upregulating COX-2 and PGD2 production in MC impacting Th2 inflammation and asthma. We will test this hypothesis in the following specific aims: 1) To determine the interplay between the known (CysLT1R and CysLT2R) and putative (GPR99, P2Y12R and PPARɣ) CysLTRs in response to cys-LTs, influencing MC function, 2) To uncover the mechanism by which cys-LT-PGE2 synergism induces PGD2 production and MC activation and 3) To determine the physiological significance of cys-LT+PGE2 interactions and MC in pulmonary inflammation in vivo. We will analyze pathologic, physiologic, and immunologic signatures of the immune response and evaluate the contribution of MCs. These studies will carry substantial pathogenic and therapeutic implications for asthma and allergic diseases as well as provide the basis for development and translation of future therapeutic molecules that regulate inflammation.


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 = -$449 )
2025	2023	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Allergy and Infectious Diseases Research	000	6	6/9/2025	NON-COMPETING CONTINUATION	-$449
														Subtotal = -$449

Issue Date FY: 2023 ( Subtotal = $362,276 )
2023	2023	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Allergy and Infectious Diseases Research	000	6	1/4/2023	NON-COMPETING CONTINUATION	$362,276
														Subtotal = $362,276

Issue Date FY: 2022 ( Subtotal = $355,767 )
2022	2022	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Allergy and Infectious Diseases Research	000	5	1/31/2022	NON-COMPETING CONTINUATION	$355,767
2022	2021	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Allergy and Infectious Diseases Research	001	3	5/19/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $355,767

Issue Date FY: 2021 ( Subtotal = $353,676 )
2021	2021	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Allergy and Infectious Diseases Research	000	3	1/13/2021	NON-COMPETING CONTINUATION	$380,000
2021	2021	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Allergy and Infectious Diseases Research	002	4	8/19/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$341,344
2021	2021	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Allergy and Infectious Diseases Research	001	3	8/19/2021	NON-COMPETING CONTINUATION	-$367,668
														Subtotal = $353,676

Issue Date FY: 2020 ( Subtotal = $380,000 )
2020	2020	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Allergy and Infectious Diseases Research	000	2	1/6/2020	NON-COMPETING CONTINUATION	$380,000
														Subtotal = $380,000

Issue Date FY: 2019 ( Subtotal = $380,000 )
2019	2019	THE UNIVERSITY OF AKRON	302 BUCHTEL COMMON	AKRON	OH	44325	SUMMIT	USA	Allergy and Infectious Diseases Research	000	1	2/20/2019	NEW	$380,000
														Subtotal = $380,000

Grand Total All Awards = $1,831,270

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Integration of Leukotriene and Prostaglandin Receptor Signaling in Mast cell Activation and Pulmonary Inflammation during Asthma

Award Number: R01AI144115

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: 02/20/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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