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The role in inflammation in platelet activation and thrombosis

Award Number: K08HL146941
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/08/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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The role in inflammation in platelet activation and thrombosis - Project Summary My primary hypothesis is that GAS6/MERTK signaling is upregulated in the setting of inflammation, leading to enhanced platelet activation responses, increased platelet-leukocyte interactions, and subsequent thrombosis. Therefore, we believe inhibition of this pathway will decrease thromboinflammation. MERTK is a receptor tyrosine kinase expressed on the platelet surface that, when stimulated by its plasma-based ligand GAS6, leads to augmentation of platelet activation responses. I have shown that inhibition of this signaling axis, either by anti-MERTK small molecule inhibitor (UNC2025) or a novel soluble MERTK splice variant (iMer) decreases in vitro platelet activation in functional assays and in vivo thrombosis in murine models. I also recently demonstrated that plasma GAS6 levels were elevated in children with thrombosis compared to healthy controls, suggesting that GAS6 may also mediate thrombosis (potentially through its ability to bridge membrane-bound phosphatidylserine and MERTK). In this proposed project, I will rigorously investigate the role of inflammation in platelet activation and thrombosis, as well as the specific mechanisms by which inhibition of GAS6/MERTK signaling impacts thromboinflammation. Though I already have a strong research base in platelet activation response assays and murine models of thrombosis, this proposal provides the experimental skills and knowledge base needed to evaluate the contributions of the inflammatory system in this particular context. This additional training will allow me to continue developing as a physician-scientist and execute the transition to an independent basic- translational research career in thromboinflammation. Herein, I propose three specific aims to 1) characterize the effect of inflammation upon GAS6/MERTK signaling and subsequent platelet activation in vitro and thrombosis in vivo, 2) define the mechanism through which GAS6/MERTK signaling impacts thromboinflammation, and 3) determine the role of iMer in regulating GAS6/MERTK signaling in platelets. My mentorship team consists of recognized leaders in functional assays of platelet activation and murine models of thrombosis (Dr. Jorge Di Paola, primary mentor), and cell-cell interactions in the setting of inflammation (Dr. Sean Colgan, co-mentor). The training plan clearly outlines how I will advance my research career development by building upon my previous studies and experience using the proposed research aims, didactic course-work, attendance at local and national meeting, and guidance from my mentorship team and scholarship oversight committee. I specifically designed the proposed project and associated career development plan to facilitate my transition to independent investigator with the long-term goal of developing novel strategies to decrease inflammation-related thrombosis.


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 = $0 )
2025	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	5	4/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $162,043 )
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	5	1/23/2024	NON-COMPETING CONTINUATION	$162,043
														Subtotal = $162,043

Issue Date FY: 2023 ( Subtotal = $162,043 )
2023	2023	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	4	11/23/2022	NON-COMPETING CONTINUATION	$162,043
														Subtotal = $162,043

Issue Date FY: 2022 ( Subtotal = $162,043 )
2022	2022	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	000	3	12/31/2021	NON-COMPETING CONTINUATION	$162,043
														Subtotal = $162,043

Issue Date FY: 2021 ( Subtotal = $162,043 )
2021	2021	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	003	2	6/26/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$70,807
2021	2021	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Blood Diseases and Resources Research	001	2	1/28/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$162,043
2021	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Blood Diseases and Resources Research	002	1	6/26/2021	NEW	-$70,807
2021	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Blood Diseases and Resources Research	000	1	1/28/2021	NEW	$0
														Subtotal = $162,043

Issue Date FY: 2020 ( Subtotal = $162,043 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Blood Diseases and Resources Research	000	1	1/7/2020	NEW	$162,043
														Subtotal = $162,043

Grand Total All Awards = $810,215

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The role in inflammation in platelet activation and thrombosis

Award Number: K08HL146941

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/08/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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