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Molecular and Translational Studies in Hematologic Disorders

Award Number: R35HL145262
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Molecular and Translational Studies in Hematologic Disorders - This application for an NHLBI R35 Outstanding Investigator Award is to explore the role of the plasma protein von Willebrand factor (VWF) in 2 diseases, type 2 von Willebrand disease (VWD) and sickle cell disease (SCD), and our goal is to roll 2 R01 grants covering these areas into a single, more cohesive grant with more flexibility to follow interesting scientific leads. In these two diseases, the involvement of VWF is in opposite directions, dysfunctional and with predominantly small multimers in type 2 VWD, and abundant, hyperfunctional, and large in sickle cell disease. For VWD, we will explore the molecular basis of the broad phenotypic variability associated with single mutations, testing the hypothesis that important determinants of this variability include percentage of mutant monomer incorporation into multimeric VWF and extent of VWF proteolysis by the met- alloprotease ADAMTS13. We will also explore how platelet contractility is affected in type 2 VWD, including to determine the respective contributions of plasma and platelet VWF. Finally, we will examine the intriguing possibility that in types 2A and 2B VWD a significant contribution to the hemostatic defect is provided by VWF fragments produced by excessive VWF proteolysis. In SCD, we have evidence of defective regulation of the largest VWF multimers, which are inadequately cleaved by ADAMTS13. We will investigate the basis of this lesion, and test whether a variety of measures aimed at attenuating the activity of VWF will improve the course of the disease in an animal model of SCD. Finally, we will explore the molecular basis of a fascinating observation we made in the course of studying the effect of N-acetylcysteine in SCD: that the drug induced rapid loss of very dense erythrocytes from the blood of patients. We hypothesize that the effect is caused by reduction of oxidized spectrin residues and will also explore the possibility that it may be treated even more effectively by the amino acid L-ergothioneine, which is present in mushrooms and other foods and is concen- trated in erythrocytes by a highly specific transporter. Together, these studies use state-of-the-art tools to ex- plore perplexing problems in two important human diseases, with the expectation of improved therapies for the affected patients. The R35 funding mechanism provides the flexibility to follow interesting leads discov- ered during the course of these studies, increasing the likelihood that patients will benefit.


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 = -$2 )
2025	2024	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	001	6	2/24/2025	NON-COMPETING CONTINUATION	$0
2025	2024	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	000	6	11/18/2024	NON-COMPETING CONTINUATION	$0
2025	2024	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	002	6	7/2/2025	NON-COMPETING CONTINUATION	-$2
														Subtotal = -$2

Issue Date FY: 2024 ( Subtotal = $1,052,245 )
2024	2024	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	001	6	6/21/2024	NON-COMPETING CONTINUATION	$85,897
2024	2024	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	000	6	3/4/2024	NON-COMPETING CONTINUATION	$966,348
														Subtotal = $1,052,245

Issue Date FY: 2023 ( Subtotal = $1,080,109 )
2023	2023	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	001	5	8/10/2023	NON-COMPETING CONTINUATION	$0
2023	2023	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	000	5	2/20/2023	NON-COMPETING CONTINUATION	$1,080,109
														Subtotal = $1,080,109

Issue Date FY: 2022 ( Subtotal = $1,081,020 )
2022	2022	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	000	4	3/17/2022	NON-COMPETING CONTINUATION	$972,915
2022	2022	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	001	4	6/17/2022	NON-COMPETING CONTINUATION	$108,105
														Subtotal = $1,081,020

Issue Date FY: 2021 ( Subtotal = $1,083,722 )
2021	2021	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	000	3	3/29/2021	NON-COMPETING CONTINUATION	$1,083,722
														Subtotal = $1,083,722

Issue Date FY: 2020 ( Subtotal = $1,084,583 )
2020	2020	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	000	2	2/25/2020	NON-COMPETING CONTINUATION	$1,084,583
														Subtotal = $1,084,583

Issue Date FY: 2019 ( Subtotal = $1,105,665 )
2019	2019	BLOODWORKS	921 TERRY AVE	SEATTLE	WA	98104	KING	USA	Blood Diseases and Resources Research	000	1	3/15/2019	NEW	$1,105,665
														Subtotal = $1,105,665

Grand Total All Awards = $6,487,342

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Molecular and Translational Studies in Hematologic Disorders

Award Number: R35HL145262

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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