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Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome

Award Number: R01HL128297
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome - PROJECT SUMMARY Acute chest syndrome (ACS) is a type of lung vascular injury and a leading cause of mortality in Sickle Cell Disease (SCD). The etiological mechanism that triggers ACS remains poorly understood and the current therapy for ACS is primarily supportive. SCD patients hospitalized with acute systemic painful vaso-occlusive episodes often develop ACS within the next few days, suggesting that molecular events surrounding lung vascular occlusion (vaso-occlusion) contribute to lung injury. This epidemiology also offers a therapeutic window to halt the development of ACS, provided targeted therapies are identified. In the last cycle of this R01, we discovered a novel P-selectin independent mechanism of ACS. We revealed that type-I interferon (type-I IFN) signaling in neutrophils promotes Gasdermin-D (GSDMD)-dependent but P-selectin-independent shedding of neutrophil extracellular traps (NETs). These NETs promote micro-embolism of precapillary pulmonary arterioles (lung vaso- occlusion) by neutrophil-platelet aggregates, leading to the arrest of blood flow and vascular injury in the lung of SCD mice. These findings have been published in Blood 2022 & 2021, Haematologica 2024, JCI-Insight 2024, Science Advances 2022, and several other articles. In the present renewal of our R01, we identify a new platelet- dependent mechanism responsible for IFN- and  (type-I IFNs) production in neutrophils, which can be targeted to prevent NETs generation and lung vaso-occlusion in SCD. Based on our new preliminary findings, we hypothesize that activation of STING signaling in platelets promotes the release of pIRF3 containing (pIRF3+) extracellular vesicles (EVs) by platelets in SCD. We also propose that these platelet-EVs transfer pIRF3 (a transcription factor) to neutrophils to promote type-I IFN production and NETs generation by neutrophils, and inhibiting STING activation in platelets will prevent development of ACS in SCD. We will test this hypothesis using our model of intravenous hemoglobin induced ACS in SCD mice, in vivo imaging of lung in live mice, in vitro microfluidic studies with patient blood, nanoparticle tracking analysis of EVs, and SCD mice genetically deficient in GSDMD or lacking IFNAR1 only in neutrophils or STING/IRF3 only in platelets. In Aim 1, we will determine whether type-I IFN production in neutrophils promotes GSDMD-dependent NETs generation and development of ACS in SCD. In Aim 2, we will determine whether delivery of pIRF3 by platelet-EVs promotes type-I IFN production in neutrophils and development of ACS in SCD. In Aim 3, we will determine whether STING activation in platelets promotes the release of pIRF3+ platelet-EVs and development of ACS in SCD. This study will introduce a novel paradigm that EV-mediated transfer of transcription factors from platelets to neutrophils promotes lung vascular injury and identify a new platelet-STING dependent mechanism of ACS in SCD.


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 = $1,505,882 )
2025	2025	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	002	10	9/23/2025	COMPETING CONTINUATION	$1,505,882
2025	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	9	9/22/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	9	10/22/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $1,505,882

Issue Date FY: 2024 ( Subtotal = $511,476 )
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	004	9	7/8/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$600,493
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	9	6/14/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$511,476
2024	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	8	6/12/2024	NON-COMPETING CONTINUATION	$0
2024	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	003	8	7/8/2024	NON-COMPETING CONTINUATION	-$498,844
2024	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	002	7	7/8/2024	NON-COMPETING CONTINUATION	-$101,649
														Subtotal = $511,476

Issue Date FY: 2023 ( Subtotal = $498,844 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	8	5/15/2023	NON-COMPETING CONTINUATION	$498,844
														Subtotal = $498,844

Issue Date FY: 2022 ( Subtotal = $498,201 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	002	7	5/23/2022	NON-COMPETING CONTINUATION	$498,201
2022	2021	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	001	6	11/21/2021	COMPETING CONTINUATION	$85
2022	2019	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	5	11/21/2021	NON-COMPETING CONTINUATION	-$85
														Subtotal = $498,201

Issue Date FY: 2021 ( Subtotal = $491,126 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	6	4/9/2021	COMPETING CONTINUATION	$442,015
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	001	6	6/10/2021	COMPETING CONTINUATION	$49,111
														Subtotal = $491,126

Issue Date FY: 2019 ( Subtotal = $372,845 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	000	5	5/21/2019	NON-COMPETING CONTINUATION	$372,845
														Subtotal = $372,845

Issue Date FY: 2018 ( Subtotal = $373,199 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	000	4	5/13/2018	NON-COMPETING CONTINUATION	$373,199
														Subtotal = $373,199

Issue Date FY: 2017 ( Subtotal = $373,542 )
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	000	3	6/2/2017	NON-COMPETING CONTINUATION	$373,542
														Subtotal = $373,542

Issue Date FY: 2016 ( Subtotal = $373,876 )
2016	2016	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	000	2	5/13/2016	NON-COMPETING CONTINUATION	$373,876
														Subtotal = $373,876

Issue Date FY: 2015 ( Subtotal = $374,200 )
2015	2015	UNIVERSITY OF PITTSBURGH	123 UNIVERSITY PLACE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Blood Diseases and Resources Research	000	1	8/7/2015	NEW	$374,200
														Subtotal = $374,200

Grand Total All Awards = $5,373,191

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Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome

Award Number: R01HL128297

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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