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Studies of Physiologic and Pathologic Platelet Plug Formation

Award Number: P01HL146373
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/10/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Studies of Physiologic and Pathologic Platelet Plug Formation - PROGRAM INTRODUCTION SUMMARY: This is the re-submission of a new Program Project (HL146373-01) that we have re-named “Studies of Physiologic and Pathologic Platelet Plug Formation” to more accurately reflect the topics the Program Project addresses. In addition to forming hemostatic plugs at sites of vascular injury, platelets make important contributions to processes such as inflammation, tissue regeneration, host defense, angiogenesis, lymphatic development, and tumor metastasis. Pathologic platelet thrombi are also responsible for much of the morbidity and mortality of arterial vascular disease. There remain large gaps in our understanding of physiologic and pathologic platelet function. Building upon our collective scientific accomplishments, we address these gaps using the cell-biologic, structural-biologic, and computational-biologic methods we have developed. The Program Project we propose consists of four projects and one administrative core unit. All of the projects are based at the Perelman School of Medicine of the University of Pennsylvania. Three projects are based in the Hematology-Oncology Division of the Department of Medicine; the fourth is based in the Division of Hematology of the Department of Pediatrics at The Children's Hospital of Philadelphia. Project 1, re-named “Novel Roles for Phosphoinositide Signaling in α-Granule Biogenesis”, is based on the hypotheses that phosphoinositide synthesis is an essential step in the loading of α-granules with components synthesized in the Golgi and that megakaryocyte phosphoinositides play a previously unrecognized role in the development of congenital megakaryocyte disorders. The objectives of Project 2, entitled “Platelet Integrin Structure and Function”, are to use novel computational and experimental techniques to compare the behavior of αIIbβ3 with that of the other integrins and to identify and quantify the protein-protein interactions responsible for αIIbβ3-mediated fibrin clot contraction. Project 3 is entitled “A Systems Approach to Hemostasis and Thrombosis“. The goals of the studies proposed in this Project are to extend past analyses of platelet thrombus formation and structure from the microvasculature to the macrovasculature, from mice to humans, and from hemostasis to thrombosis. Project 4, entitled “Platelet Factor 4 and Heparin in NETosis and Sepsis”, will test the hypothesis that NETs, neutrophil extracellular traps composed of chromatin released by neutrophils, require partial digestion and release of DNA and histones to be toxic during sepsis. Because infused platelet factor 4, as well as the monoclonal antibody KKO that binds to the complex of platelet factor 4 and heparin, block DNA digestion, both will be protective in sepsis. The four projects are supported by a single core unit that provides for the common administrative needs of the Program.


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: 2024 ( Subtotal = $2,371,610 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	5	8/26/2024	NON-COMPETING CONTINUATION	$2,371,610
														Subtotal = $2,371,610

Issue Date FY: 2023 ( Subtotal = $2,439,527 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	4	5/3/2023	NON-COMPETING CONTINUATION	$2,439,527
														Subtotal = $2,439,527

Issue Date FY: 2022 ( Subtotal = $2,458,478 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Blood Diseases and Resources Research	001	3	6/30/2022	NON-COMPETING CONTINUATION	$2,458,478
2022	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	2	4/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,458,478

Issue Date FY: 2021 ( Subtotal = $2,353,637 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Blood Diseases and Resources Research	001	2	6/18/2021	NON-COMPETING CONTINUATION	$2,463,703
2021	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	1	10/30/2020	NEW	-$110,066
														Subtotal = $2,353,637

Issue Date FY: 2020 ( Subtotal = $2,533,144 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	1	5/8/2020	NEW	$2,533,144
														Subtotal = $2,533,144

Grand Total All Awards = $12,156,396

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Studies of Physiologic and Pathologic Platelet Plug Formation

Award Number: P01HL146373

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/10/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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