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Small GTPases in the biology of platelets and megakaryocytes

Award Number: R35HL144976
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/21/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Small GTPases in the biology of platelets and megakaryocytes - ABSTRACT Mammalian platelets are small anucleate blood cells specialized to continuously monitor and preserve the integrity of the cardiovascular system (hemostasis). They are produced by megakaryocytes (MKs) in the bone marrow and released into blood, where they circulate for ten days in humans and five days in mice until they get cleared by phagocytes. Platelet homeostasis, i.e. the establishment of a defined peripheral platelet count, requires tight regulation of both platelet production and clearance. To fulfill their hemostatic function, platelets depend on a very sensitive signaling machinery that facilitates platelet adhesion under shear stress. This high sensitivity, however, poses a risk for unwanted platelet activation that can lead to platelet clearance and/or thrombosis. The overarching goal of our work is to achieve a better understanding of the molecular mechanisms regulating MK development and platelet reactivity, with a specific focus on the role of small GTPases in these processes. This R35 OIA application is an extension to three funded NHLBI R01 grants: Small GTPases in Megakaryocyte Biology; Rap1 Signaling in Platelet Homeostasis and Vascular Hemostasis; Spatial Regulation of Platelet Activation by Podoplanin-Clec2 Signaling. Our MK studies utilize unique biosensors to establish a molecular signature of small GTPase activity (both Rho and Rap GTPases) during the final stages of development, including the transition from proliferation to proplatelet formation. Once established, we will establish proof-of-principle that precisely targeted perturbation of GTPase activity by optogenetic tools is a viable strategy to optimize in vitro platelet production, a hot topic in Transfusion Medicine. Our platelet work focuses more specifically on the role of Rap GTPases as master regulators of cellular activation and hemostatic plug formation. We have utilized unique mouse models to establish the importance and the key regulators of Rap1 signaling during platelet activation. Furthermore, we have shown that Rap1 activity has to be tightly balanced both in quiescent, circulating and in hemostatically active platelets, and that disturbance of this pathway leads to bleeding or thrombocytopenia/ thrombosis. In ongoing and future work, we will expand on our cell biological and biochemical/-physical studies to provide a comprehensive understanding of how Rap signaling controls platelet function, how it is regulated, and if/ how it contributes to other patho-physiological processes such as vascular integrity in development/ inflammation and venous thrombosis. We will use our unique biochemical assays to screen for inhibitors of Rap signaling. Our clinical studies will investigate if Rap1 signaling is altered in various pathologies, and whether there is interindividual variability in this pathway in healthy and diseased subjects? Together, these studies are expected to lead to novel strategies for the diagnosis and management of some inherited and acquired thrombocytopenias and bleeding disorders, and to a more personalized approach to anti-platelet therapy.


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 = $842,128 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	7	3/17/2025	NON-COMPETING CONTINUATION	$757,916
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	001	7	8/5/2025	NON-COMPETING CONTINUATION	$84,212
														Subtotal = $842,128

Issue Date FY: 2024 ( Subtotal = $825,286 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	6	3/4/2024	NON-COMPETING CONTINUATION	$757,916
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	001	6	6/21/2024	NON-COMPETING CONTINUATION	$67,370
														Subtotal = $825,286

Issue Date FY: 2023 ( Subtotal = $842,128 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	5	2/27/2023	NON-COMPETING CONTINUATION	$842,128
														Subtotal = $842,128

Issue Date FY: 2022 ( Subtotal = $842,128 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	4	2/22/2022	NON-COMPETING CONTINUATION	$757,913
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	001	4	6/15/2022	NON-COMPETING CONTINUATION	$84,215
														Subtotal = $842,128

Issue Date FY: 2021 ( Subtotal = $842,128 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	3	3/24/2021	NON-COMPETING CONTINUATION	$842,128
														Subtotal = $842,128

Issue Date FY: 2020 ( Subtotal = $623,573 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	2	3/4/2020	NON-COMPETING CONTINUATION	$623,573
														Subtotal = $623,573

Issue Date FY: 2019 ( Subtotal = $561,180 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Blood Diseases and Resources Research	000	1	3/22/2019	NEW	$561,180
														Subtotal = $561,180

Grand Total All Awards = $5,378,551

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Small GTPases in the biology of platelets and megakaryocytes

Award Number: R35HL144976

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/21/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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