LICAMM Investigation of inflammation driven bone marrow reprogramming and its contribution to thrombotic risk

Summary

Inflammatory conditions are associated with increased risk of cardiovascular disease and thrombotic events. Platelets are initiators and drivers of arterial thrombosis and inflammation is associated with dysregulated platelet production and platelet hyperreactivity. Understanding these inflammation-driven changes is essential for the development of anti-thrombotic therapy with improved efficacy in individuals with chronic inflammatory conditions.

Platelets are produced by megakaryocytes that reside in the bone marrow and produce platelets via a process called thrombopoiesis that is driven by thrombopoietin. Accelerated, reduced and abnormal thrombopoesis have implications for normal physiology, with thrombocytopenia associated with bleeding and thrombocytosis with thrombosis. In many inflammatory conditions platelet counts increase, due to accelerated thrombopoieisis and reactive thrombocytosis, resulting in the production of larger more reactive platelets, leading to platelet hyperreactivity and thrombosis. Inflammatory cues, including interleukins 1 (IL-1), IFN-γ, IL-6, CCL5 and tumor necrosis factor-α (TNF-α) are often elevated in inflammatory conditions and have been shown to regulate platelet production during hematopoietic stress. These inflammation driven alterations in megakaryocyte biology and subsequent production of phenotypically different platelets that are hyper-reactive may lower the threshold for induction of thrombosis. What initiates this up-regulation in number and function, whilst thought to be attributed to increased circulating cytokine levels, is not well understood and cellular mechanisms remain to be elucidated.

This project aims to:

1. Determine the effect of inflammatory cytokines on megakaryocyte biology and maturation.
2. Characterise the role of inflammatory cytokines in the process of platelet production.
3. Investigate changes to platelet reactivity and thrombotic potential in response to exposure to inflammatory cytokines.

This project will involve the use of both in vitro and in vivo models. In this project you will develop a comprehensive skill set crucial for future research. This includes expertise in cell culture, flow cytometry, fluorescent microscopy, ELISAs and Western blotting, in addition to platelet function and in vitro thrombus formation assays. There will also be opportunities to be trained in performing transcriptomic and proteomic analysis providing you with an excellent opportunity to build your bioinformatic skill set. In this project you will also gain an appreciation of the NC3Rs and will receive specific NC3Rs focused training, including use of the NC3Rs experimental design assistant tool, to understand the important of reducing and refining the use of animals in research.

References:

1. Machlus KR, Johnson KE, Kulenthirarajan R, et al. CCL5 derived from platelets increases megakaryocyte proplatelet formation. Blood. Feb 18 2016;127(7):921-6. doi:10.1182/blood-20
2. Cunin P, Nigrovic PA. Megakaryocytes as immune cells. J Leukoc Biol. 2019 Jun;105(6):1111-1121. doi: 10.1002/JLB.MR0718-261RR 15-05-644583
3. Unsworth AJ, Bye AP, Sage T, Gaspar RS, Eaton N, Drew C, Stainer A, Kriek N, Volberding PJ, Hutchinson JL, Riley R, Jones S, Mundell SJ, Cui W, Falet H, Gibbins JM. Antiplatelet properties of Pim kinase inhibition are mediated through disruption of thromboxane A2 receptor signaling. Haematologica. 2021 Jul 1;106(7):1968-1978. doi: 10.3324/haematol.2019.223529.
   

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject is desirable, but not essential.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5