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Endoplasmic Reticulum Stress Signaling in Allergen-induced Airway Remodeling

Award Number: R01HL122383
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2015
PERIOD OF PERFORMANCE END DATE: 10/31/2024

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Endoplasmic Reticulum Stress Signaling in Allergen-induced Airway Remodeling - PROJECT SUMMARY Severe allergic asthma is marked by airway inflammation, remodeling, and hyperresponsiveness, which correlates with decreased lung function and increased mortality. We have identified the endoplasmic reticulum (ER) based unfolded protein response (UPR) as a critical mediator of lung epithelial inflammatory and fibrotic responses to allergens. Recent reports highlight that increases in the UPR pathways are potentially classified as an endotype of severe asthma. However, the mechanisms whereby the UPR response is initiated and perpetuated in settings of severe asthma remain unaddressed, and will be the focus of this application. Our novel preliminary results now suggest that allergen challenge increases reactive oxygen species (ROS) in the ER and oxidative modification of cysteines in GRP78. Oxidation of GRP78 resultes in dissociation of GRP78 and causes initial activation of the UPR transducer, ATF6. We observed that the ATF6 target, PDIA5, was also significantly upregulated in both asthmatics and a mouse asthma model in association with an enhanced allergic responses in lungs. Intriguingly, PDIA5 reduces cysteines disulfides to (-S-S-) to sulfhydryls (-SH) of ATF6, which is suggestive of a feed-forward regulatory mechanism to sustain the UPR. Based on these observations, we hypothesize that allergen-induced oxidation of GRP78 initiates the UPR signaling, with subsequent increases in PDIA5 prolong the UPR and thereby increasing allergic airway responses. To examine this hypothesis, we propose the following specific aims: In Specific Aim #1 we will determine the functional role of allergen-induced reactive oxygen species and subsequent oxidation of GRP78 in initiation of the UPR, expression of cytokines/chemokines, and subsequent induction of pro-inflammatory response and development of lung remodeling. The specific Aim #2 seeks to dissect the critical requirement of allergen-induced PDIA5 in disulfide mediated processing of a transducer of UPR ATF6 in severe allergic airway responses. In both aims we will use transgenic mouse models, cell culture and sensitive redox and biochemical assays. Most importantly we will examine the efficacy of specific inhibitors of ATF6α (Ceapin-A7) and PDIA5 (LOC14) in attenuating allergen-induced UPR, decreasing subsequent pro- inflammatory responses, and ultimately resulting in resolution of allergen-induced lung pathology. These studies will shed light on the importance of the allergen-induced lung epithelial UPR in pro-inflammatory responses, lung remodeling and offers insight into new and highly needed treatment modalities for severe allergic airway disease beyond supportive care.


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 = $0 )
2025	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	9	2/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $390,000 )
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	9	5/23/2023	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2022 ( Subtotal = $390,000 )
2022	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	8	5/16/2022	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2021 ( Subtotal = $390,000 )
2021	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	7	4/16/2021	NON-COMPETING CONTINUATION	$390,000
2021	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	001	5	6/18/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $390,000

Issue Date FY: 2020 ( Subtotal = $390,000 )
2020	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	001	6	5/1/2020	COMPETING CONTINUATION	$390,000
2020	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	5	4/27/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $390,000

Issue Date FY: 2019 ( Subtotal = $381,250 )
2019	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	5	1/16/2019	NON-COMPETING CONTINUATION	$381,250
														Subtotal = $381,250

Issue Date FY: 2018 ( Subtotal = $381,250 )
2018	2018	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	001	4	6/16/2018	NON-COMPETING CONTINUATION	$7,625
2018	2018	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	4	1/10/2018	NON-COMPETING CONTINUATION	$373,625
														Subtotal = $381,250

Issue Date FY: 2017 ( Subtotal = $381,250 )
2017	2017	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	3	12/15/2016	NON-COMPETING CONTINUATION	$381,250
														Subtotal = $381,250

Issue Date FY: 2016 ( Subtotal = $381,250 )
2016	2016	UNIVERSITY OF VERMONT	223 WATERMAN BUILDING	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	001	2	3/18/2016	NON-COMPETING CONTINUATION	$5,719
2016	2016	UNIVERSITY OF VERMONT	223 WATERMAN BUILDING	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	2	12/28/2015	NON-COMPETING CONTINUATION	$375,531
														Subtotal = $381,250

Issue Date FY: 2015 ( Subtotal = $381,250 )
2015	2015	UNIVERSITY OF VERMONT	223 WATERMAN BUILDING	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	1	12/23/2014	NEW	$381,250
														Subtotal = $381,250

Grand Total All Awards = $3,466,250

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Endoplasmic Reticulum Stress Signaling in Allergen-induced Airway Remodeling

Award Number: R01HL122383

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2015

PERIOD OF PERFORMANCE END DATE: 10/31/2024

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