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Targeting Type-2 mucoinflammatory axis during the resolution of allergic lung inflammation

Award Number: R01ES035439
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/22/2024
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Targeting Type-2 mucoinflammatory axis during the resolution of allergic lung inflammation - Project Summary Allergic asthma results in predominantly type-2 (Th2) mucoinflammatory responses including granulocytic inflammation and respiratory epithelial remodeling. These features are also consistently observed in the respiratory tract of rodents exposed repetitively to ozone. Therefore, the ozone-predominated air pollution during the resolution phase of allergic asthma may interfere with the restoration of structure and function in the allergic nasal and pulmonary airspaces. Currently, the molecular and cellular level understanding of the pathogenesis and resolution of either ozone- or allergens-induced Th2 mucoinflammatory respiratory responses has significant knowledge gaps. Therefore, detailed studies addressing these knowledge gaps are essential in promoting our understanding of the interference between ozone pollution and the resolution of allergic inflammation in asthma. Our central hypothesis is that IL-33 regulates the pathogenesis of Th2 inflammation in a cell lineage-specific manner and that targeting of IL-33-ST2 axis will mitigate active inflammation and promote the resolution of mucoinflammatory respiratory disease. The overall objective of this proposal is to test the benefit of inhibition of IL33-ST2 signaling during the pathogenesis and resolution of ozone- and allergens-induced respiratory (nasal and lung) inflammation. In aim 1, we will employ cross-genotype bone marrow chimera approach to elucidate the autocrine versus paracrine IL-33 signaling between hematopoietic progenitor cells (HPCs) and non-HPCs during active ozone/allergens-induced respiratory inflammation. In aim 2, we will test our hypothesis that ozone-exposure disrupts the resolution kinetics of allergens-induced respiratory inflammation. In aim 3, we will test the hypothesis that the genetic and pharmacological inhibition of IL-33-ST2 axis neutralizes ozone-mediated disruption in the resolution of allergens-induced respiratory inflammation. The findings from our studies will enhance our mechanistic understanding of the cell lineage- and signaling direction-specific role of the upstream master regulator of ozone/allergens-induced respiratory inflammation. Impact of ozone on the resolution kinetics of allergic inflammation and the potential for the genetic and pharmacological expedition of ozone-disrupted resolution of allergic airway inflammation will have translational impact. Eventually, these findings may be applied towards the development of anti-inflammation and pro-resolution therapeutics against air-pollution induced Th2 inflammatory diseases.


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 = $558,696 )
2025	2025	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Environmental Health	000	2	10/28/2024	NON-COMPETING CONTINUATION	$558,696
														Subtotal = $558,696

Issue Date FY: 2024 ( Subtotal = $571,696 )
2024	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Environmental Health	000	1	1/19/2024	NEW	$571,696
														Subtotal = $571,696

Grand Total All Awards = $1,130,392

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Targeting Type-2 mucoinflammatory axis during the resolution of allergic lung inflammation

Award Number: R01ES035439

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/22/2024

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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