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Restoration and Function of S-Nitrosothiol in Stored Blood

Award Number: R01HL126900
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2016
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Restoration and Function of S-Nitrosothiol in Stored Blood - PROJECT SUMMARY The therapeutic benefit of transfusion presumes a direct correlation between blood oxygen carrying capacity and oxygen delivery. However, our preclinical and clinical studies show that stored blood loses its ability to oxygenate tissues. The sequelae that can occur after transfusion (renal injury, myocardial infarction, death) are consistent with the idea that banked blood may exacerbate rather than correct anemia-induced hypoxia. We have discovered that banked blood has markedly diminished levels of nitric oxide/S-nitrosothiol (NO/SNO) bioactivity including the S-nitrosylated form of hemoglobin (SNO-Hb), a major mediator of blood flow and peripheral oxygen delivery. This decline in SNO provides a mechanistic basis for the impaired vasodilatory activity of stored red blood cells (RBCs) and an explanation for why transfusion of even small amounts of blood may impair tissue perfusion. We have built on this novel finding by demonstrating that restoration of SNO-Hb levels (renitrosylation) corrects storage-induced deficiencies in RBC oxygen delivery and transfusion-induced organ dysfunction in multiple preclinical transfusion paradigms, and we have initiated clinical studies to assess the effects of transfusion on tissue oxygenation. We have also developed first-in-class renitrosylating agents that are already undergoing clinical testing. We are positioned to provide critically needed data on the effects of transfusion on tissue oxygenation in humans and to advance the benefits of renitrosylation therapy on oxygen delivery through the following aims: 1. To further advance understanding of the molecular mechanisms by which RBCs export SNO bioactivity to regulate tissue oxygenation; 2. To develop a device for controlled ex vivo renitrosylation; 3. To determine if renitrosylation can improve post-surgical outcome in an animal model of pediatric bypass; and 4. To conduct an autologous transfusion study in humans to determine the benefits of renitrosylation on tissue oxygenation. Collectively, our studies should provide much-needed insight into the effects of transfusion on tissue oxygenation, shed light on the mechanistic basis of adverse ischemic events associated with transfusion, and accelerate development of therapeutic approaches (repletion of SNO-Hb). Restoration of the oxygen delivery capabilities of banked blood should result in blood transfusion achieving its clinical purpose: vasodilation in the microcirculation to improve end-organ oxygen delivery in the anemic patient. To the extent that the world’s supplies of banked RBCs are deficient in SNO-Hb, renitrosylation may hold significant therapeutic promise.


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 = $567,229 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	001	8	7/16/2025	NON-COMPETING CONTINUATION	$56,724
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	8	3/7/2025	NON-COMPETING CONTINUATION	$510,505
														Subtotal = $567,229

Issue Date FY: 2024 ( Subtotal = $555,884 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	002	7	6/20/2024	NON-COMPETING CONTINUATION	$45,379
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	001	7	1/30/2024	NON-COMPETING CONTINUATION	$510,505
2024	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	5	11/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $555,884

Issue Date FY: 2023 ( Subtotal = $567,229 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	6	3/31/2023	COMPETING CONTINUATION	$567,229
														Subtotal = $567,229

Issue Date FY: 2020 ( Subtotal = $549,410 )
2020	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	5	6/15/2020	NON-COMPETING CONTINUATION	$549,410
														Subtotal = $549,410

Issue Date FY: 2019 ( Subtotal = $549,410 )
2019	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	4	7/26/2019	NON-COMPETING CONTINUATION	$549,410
														Subtotal = $549,410

Issue Date FY: 2018 ( Subtotal = $549,410 )
2018	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	3	7/1/2018	NON-COMPETING CONTINUATION	$549,410
														Subtotal = $549,410

Issue Date FY: 2017 ( Subtotal = $549,410 )
2017	2017	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	2	7/17/2017	NON-COMPETING CONTINUATION	$549,410
														Subtotal = $549,410

Issue Date FY: 2016 ( Subtotal = $565,855 )
2016	2016	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	1	5/31/2016	NEW	$565,855
														Subtotal = $565,855

Grand Total All Awards = $4,453,837

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Restoration and Function of S-Nitrosothiol in Stored Blood

Award Number: R01HL126900

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2016

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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