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Platelet Integrin AlphaIIbBeta3 Structure, Activation, and Ligand Binding: Fibrinogen, Fibrin, D-dimer, and von Willebrand Factor

Award Number: R01HL019278
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Platelet Integrin AlphaIIbBeta3 Structure, Activation, and Ligand Binding: Fibrinogen, Fibrin, D-dimer, and von Willebrand Factor - Project Summary/Abstract Platelets play a key role in both hemostasis and thrombosis and contribute to COVID-19 pathology. Platelet αIIbβ3 is the paradigmatic integrin receptor and a validated drug target, with abciximab, developed under this grant, the first FDA-approved αIIbβ3 antagonist. In the current grant period, we rationally designed and synthesized novel αIIbβ3 and αVβ3 antagonists that lock the receptor in the inactive conformation, which may confer therapeutic benefits. The αIIbβ3 antagonist (RUC-4; zalunfiban) is now in Phase 2 human studies for pre- hospital therapy of heart attacks and the αVβ3 antagonists are being developed for pre-clinical testing. We also began studying key gaps in our understanding of how αIIbβ3: 1. Binds its medically important ligands, including fibrinogen, polymerizing fibrin, von Willebrand factor (vWf), and cross-linked fibrin. 2. Initiates clot retraction to confer resistance to thrombolysis. 3. Transitions from its inactive to its active state. Thus, we studied the interaction of αIIbβ3 with fragment D-dimer and used a novel functional assay to dissect the interaction of αIIbβ3 with polymerizing fibrin. In addition, we obtained high-resolution cryo-electron microscopy (EM) structures of αIIbβ3 in complex with abciximab and with the activating monoclonal antibody (mAb) PT25-2, providing data on each antibody’s mechanism of activation. We also initiated hydrogen-deuterium exchange-mass spectroscopy (HDX) studies of αIIbβ3 to provide peptide-level dynamic structural information on ligand binding and receptor activation to complement cryo-EM data. The new Specific Aims build on the PI’s long-standing collaborations with Dr. Marta Filizola, an expert in computational methods, and Dr. Thomas Walz, an expert in cryo-EM. Specific Aim 1. A. To determine high-resolution cryo-EM structures of D-dimer and of αIIbβ3 in complex with: 1) fibrinogen fragment D100 and fibrinogen γ-module; 2) vWf C4 domain; 3) D-dimer. B. To obtain peptide- level solvent-exposed area data by HDX on αIIbβ3 alone and in complex with the ligands. C. To obtain complementary structural and dynamics information from computer simulations to guide mutational analysis and mAb production to validate the proposed mechanisms of binding, as well as to develop novel ligand-specific small-molecule antagonists. Specific Aim 2. To utilize currently available and future cryo-EM data sets in concert with computational and HDX data to define intermediate structures of the integrin leg domains along the αIIbβ3 activation pathway. Specific Aim 3. To utilize our novel functional polymerizing fibrin assays using platelets and HEK293 cells expressing native and mutant forms of αIIbβ3, in concert with mAbs and small-molecule αIIbβ3 antagonists, to define the unique αIIbβ3 ligand-specific binding mechanisms and develop ligand-specific inhibitors. A. To produce mAbs to D-dimer that inhibit platelet-fibrin, but not platelet-fibrinogen interactions. B. To identify mutations that selectively impair fibrinogen, fibrin, or vWf binding, and examine their impact on clot retraction. C. To test predictions derived from the structural and computational studies with mAb and small- molecule ligand-specific inhibitors as a prelude to animal and ultimately human studies.


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 = $683,136 )
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	49	1/20/2025	NON-COMPETING CONTINUATION	$683,136
														Subtotal = $683,136

Issue Date FY: 2024 ( Subtotal = $743,861 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	001	48	6/20/2024	NON-COMPETING CONTINUATION	$60,725
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	48	2/5/2024	NON-COMPETING CONTINUATION	$683,136
														Subtotal = $743,861

Issue Date FY: 2023 ( Subtotal = $759,040 )
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	47	1/27/2023	NON-COMPETING CONTINUATION	$759,040
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	001	47	4/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $759,040

Issue Date FY: 2022 ( Subtotal = $776,645 )
2022	2022	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	001	46	2/3/2022	COMPETING CONTINUATION	$776,645
2022	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	45	1/31/2022	NON-COMPETING CONTINUATION	$0
2022	2020	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	002	45	5/24/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $776,645

Issue Date FY: 2020 ( Subtotal = $783,775 )
2020	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	45	5/20/2020	NON-COMPETING CONTINUATION	$783,775
														Subtotal = $783,775

Issue Date FY: 2019 ( Subtotal = $808,046 )
2019	2019	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	44	5/24/2019	NON-COMPETING CONTINUATION	$808,046
														Subtotal = $808,046

Issue Date FY: 2018 ( Subtotal = $799,129 )
2018	2018	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	002	43	5/18/2018	NON-COMPETING CONTINUATION	$799,129
2018	2017	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	001	42	11/7/2017	COMPETING CONTINUATION	$7,700
2018	2016	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	41	11/7/2017	EXTENSION WITH OR WITHOUT FUNDS	-$7,700
														Subtotal = $799,129

Issue Date FY: 2017 ( Subtotal = $848,310 )
2017	2017	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	002	42	2/7/2017	COMPETING CONTINUATION	$848,310
2017	2016	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	001	41	11/1/2016	EXTENSION WITH OR WITHOUT FUNDS	$36,042
2017	2015	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Blood Diseases and Resources Research	000	40	11/1/2016	NON-COMPETING CONTINUATION	-$36,042
														Subtotal = $848,310

Issue Date FY: 2016 ( Subtotal = $621,817 )
2016	2016	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Blood Diseases and Resources Research	000	41	5/18/2016	EXTENSION WITH OR WITHOUT FUNDS	$621,817
														Subtotal = $621,817

Issue Date FY: 2015 ( Subtotal = $612,489 )
2015	2015	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Blood Diseases and Resources Research	000	40	6/10/2015	NON-COMPETING CONTINUATION	$612,489
														Subtotal = $612,489

Issue Date FY: 2014 ( Subtotal = $609,382 )
2014	2014	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Blood Diseases and Resources Research	000	39	5/5/2014	NON-COMPETING CONTINUATION	$609,382
														Subtotal = $609,382

Issue Date FY: 2013 ( Subtotal = $615,725 )
2013	2013	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Blood Diseases and Resources Research	000	38	8/16/2013	COMPETING CONTINUATION	$615,725
														Subtotal = $615,725

Issue Date FY: 2012 ( Subtotal = $669,805 )
2012	2012	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Blood Diseases and Resources Research	000	37	6/26/2012	NON-COMPETING CONTINUATION	$669,805
														Subtotal = $669,805

Issue Date FY: 2011 ( Subtotal = $671,029 )
2011	2011	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Blood Diseases and Resources Research	000	36	6/16/2011	NON-COMPETING CONTINUATION	$671,029
														Subtotal = $671,029

Issue Date FY: 2010 ( Subtotal = $676,081 )
2010	2010	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Blood Diseases and Resources Research	000	35	6/7/2010	NON-COMPETING CONTINUATION	$676,081
														Subtotal = $676,081

Issue Date FY: 2009 ( Subtotal = $677,611 )
2009	2009	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Blood Diseases and Resources Research	000	34	6/5/2009	NON-COMPETING CONTINUATION	$677,611
														Subtotal = $677,611

Issue Date FY: 2008 ( Subtotal = $680,012 )
2008	2008	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Blood Diseases and Resources Research	000	33	9/5/2008	COMPETING CONTINUATION	$680,012
														Subtotal = $680,012

Issue Date FY: 2007 ( Subtotal = $616,958 )
2007	2007	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Blood Diseases and Resources Research	000	32	8/31/2007	NON-COMPETING CONTINUATION	$616,958
														Subtotal = $616,958

Issue Date FY: 2006 ( Subtotal = $619,630 )
2006	2006	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Blood Diseases and Resources Research	000	31	7/28/2006	NON-COMPETING CONTINUATION	$619,630
														Subtotal = $619,630

Issue Date FY: 2005 ( Subtotal = $703,378 )
2005	2005	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Blood Diseases and Resources Research	000	30	9/8/2005	NON-COMPETING CONTINUATION	$703,378
														Subtotal = $703,378

Issue Date FY: 2004 ( Subtotal = $694,196 ) (Continued on the next page)
2004	2004	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Blood Diseases and Resources Research	001	29	9/20/2004	SUPPLEMENT FOR EXPANSION	$84,292
Grand Total All Awards = $17,092,453

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Platelet Integrin AlphaIIbBeta3 Structure, Activation, and Ligand Binding: Fibrinogen, Fibrin, D-dimer, and von Willebrand Factor

Award Number: R01HL019278

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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