The role of monocyte reprogramming in chronic venous thrombosis

1 PhD project offered in the IPP winter call 2022

Scientific background

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are two manifestations of venous thromboembolism (VTE). The formation of occlusive blood clots in the venous vascular system can potentially be complicated by detachment and embolization of thrombi into the lungs, which can trigger severe consequences. DVT is associated with the risk of thromboembolic damage and long-term complications, such as post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (CTEPH). VTE leads to mortality and morbidity worldwide and especially as the population ages, the VTE incidence increases considerably. Despite initial management of symptomatic acute events, patients remain at high risk for recurrence and are predisposed to developing longer-term thrombo-inflammatory complications. The influences of the first event of DVT on the recurrence of VTE and thrombotic sequelae remain unknown. The inflammatory response induced by the thrombus formation recruits a significant number of circulating myeloid cells to the site of thrombotic damage. Recent advances suggest that the interactions of inflammatory processes with underlying cardiovascular disease may promote long-lasting functional changes in monocytes, specifically the appearance of so-called trained cells.

PhD project: The role of monocyte reprogramming in chronic venous thrombosis

In this project, we will study the effect of long-term chronic inflammation during clot growth and resolution on bone marrow myelopoiesis and monocyte profile. Therefore, we aim to systematically analyze the development of trained monocytes in thrombotic disease pathology and recurrence. Working steps consist in investigating the regulatory impact, phenotypic profiling, and functional evaluation of metabolic, epigenetic, and transcriptional alterations. The experiments will involve animal models as well as high-dimensional flow cytometry, immunohistochemistry, in vitro cell culture, chromatin immunoprecipitation assays, and unbiased molecular (single-cell) profiling approaches. This project is funded by the German Research Foundation (DFG).

Publications relevant for this project

Shahneh F, Grill A, Klein M, Bopp T, Schäfer K, Raker V, Becker C. Specialized Regulatory T Cells Control Venous Blood Clot Resolution Through SPARC. Blood, 2021. DOI: 10.1182/blood.2020005407.

Shahneh F, Probst HC, Wiesmann S, Gonzalaz N, Ruf W, Steinbrink K, Raker V, Becker C. Inflammatory Monocyte Counts Determine Venous Blood Clot Formation and Resolution. Arteriosclerosis, Thrombosis and Vascular Biology, 2021. DOI: 10.1161/ATVBAHA.121. 317176.

Luther N, Shahneh F, Brähler M, Krebs F, Kleis-Fischer B, Probst HC, Wenzel P, Schäfer K, Becker C. Innate Effector-Memory T-Cell Activation Regulates Post-Thrombotic Vein Wall Inflammation and Thrombus Resolution.  Circulation Research, 2016, DOI: 10.1161/CIRCRESAHA. 116.309301.

Contact

Dr. rer. nat Fatemeh Zare-Shahneh
Email