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Myeloid TLR4 epigenetic regulation and signaling in accelerating venous thrombus resolution

Award Number: K08HL155408
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Myeloid TLR4 epigenetic regulation and signaling in accelerating venous thrombus resolution - PROJECT ABSTRACT This proposal describes the 5-year training program for development of a research career in vascular biology, with focus on thrombosis. The candidate, Dr. Andrea Obi, has the long-term goals of becoming an independently funded surgeon-scientist, advancing understanding of immunothrombosis and reducing the morbidity from deep venous thrombosis (DVT). Dr. Obi has a strong foundation with advanced undergraduate education in Microbiology and Immunology, training in microsurgical venous thrombosis models during a T32 post-doctoral fellowship, and completion of a clinical fellowship in Vascular Surgery. A talented and experienced mentorship team provides a detailed plan of skill and scientific knowledge acquisition, and longitudinal professional development to ensure her success in developing an independent research program at the intersection of innate immunity and thrombosis. Dr. Obi's immediate goal is to leverage the K08 protected time and mentorship to develop expertise in advanced immunologic experimental techniques, solidify her scientific skill set in investigating epigenetic modifications, and to advance her knowledge in myeloid cellular signaling pathways, that will aid in developing immune based non-anticoagulant therapies for the treatment of DVT. Clinically, the presence of persistent residual venous thrombi following an episode of DVT is associated with valvular dysfunction, recurrent thrombosis and post thrombotic syndrome. Experimentally, innate immune cells, primarily monocytes/macrophages, play a central role in resolving the thrombus. In a translational mouse model we demonstrate that TLR4 is an essential mediator of thrombus resolution. Within the enclosed proposal we plan to address a major gap in clinic care, namely a lack of non-anticoagulant molecular targets for thrombus resolution, by evaluating the central hypothesis that that myeloid TLR4-mediated thrombus resolution is mechanistically driven by epigenetic changes that occur in bone marrow derived monocytes in response to acute venous thrombosis and determines the subsequent local cytokine and fibrinolytic response. This will be accomplished via three specific aims: (1) to examine the ligands, kinetics and cellular source of TLR4 and requirement for myeloid TLR4 signaling during thrombus resolution; (2) to examine the role of chromatic modifying enzyme MLL1 on postthrombotic TLR4 expression and molecular mediators of thrombus resolution; (3) to determine the feasibility of myeloid specific TLR4 agonism as a strategy to accelerate thrombus resolution and assess impact on vein wall injury.


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 = $128,829 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Blood Diseases and Resources Research	000	5	2/20/2025	NON-COMPETING CONTINUATION	$128,829
														Subtotal = $128,829

Issue Date FY: 2024 ( Subtotal = $145,800 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Blood Diseases and Resources Research	001	4	5/31/2024	NON-COMPETING CONTINUATION	-$23,760
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Blood Diseases and Resources Research	000	4	2/5/2024	NON-COMPETING CONTINUATION	$169,560
														Subtotal = $145,800

Issue Date FY: 2023 ( Subtotal = $169,560 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Blood Diseases and Resources Research	000	3	1/26/2023	NON-COMPETING CONTINUATION	$169,560
														Subtotal = $169,560

Issue Date FY: 2022 ( Subtotal = $169,462 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Blood Diseases and Resources Research	000	2	2/11/2022	NON-COMPETING CONTINUATION	$169,462
														Subtotal = $169,462

Issue Date FY: 2021 ( Subtotal = $169,472 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Blood Diseases and Resources Research	000	1	1/12/2021	NEW	$169,472
														Subtotal = $169,472

Grand Total All Awards = $783,123

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Myeloid TLR4 epigenetic regulation and signaling in accelerating venous thrombus resolution

Award Number: K08HL155408

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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