Myeloid TLR4 epigenetic regulation and signaling in accelerating venous thrombus resolution

项目摘要

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.