# Myeloid TLR4 epigenetic regulation and signaling in accelerating venous thrombus resolution

> **NIH NIH K08** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $169,462

## Abstract

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.

## Key facts

- **NIH application ID:** 10328266
- **Project number:** 5K08HL155408-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Andrea Tara Obi
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $169,462
- **Award type:** 5
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328266

## Citation

> US National Institutes of Health, RePORTER application 10328266, Myeloid TLR4 epigenetic regulation and signaling in accelerating venous thrombus resolution (5K08HL155408-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10328266. Licensed CC0.

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