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Matthew Worssam

Matthew Worssam

BHF 4-year Programme PhD Student


Research Interests

Supervisor: Dr Helle Jorgensen

Title: Assessing the impact of contractile VSMC gene expression and MAPK signalling on the heterogeneous VSMC injury response

Abstract: Hyperproliferation of vascular smooth muscle cells (VMSC) is essential in the formation of the neointimal lesions characteristic of atherosclerosis and restenosis, vascular diseases which underlie heart attack and stroke. The Jørgensen lab has identified that the VSMC contribution to neointima formation results from the clonal expansion of very few VSMCs, rather than from uniform VSMC proliferation. Several signalling pathways/transcription factors, including the MAPK pathway and Myocardin, have been identified, which when modulated alter the extent of VSMC proliferation and thus neointimal size.

I hypothesise that their modulation affects (a) the priming of VSMCs to proliferate in response to injury/inflammation and/or (b) the survival/proliferative capabilities of primed cells which activate proliferation. This will be tested by comparing the injury-induced VSMC clonal dynamics in Myocd+/- and Myocd+/+ mice by clonal lineage tracing in an explant model of vascular injury, single-cell RNA sequencing and chromatin profiling.

The relationship between Myocardin and MAPK signalling in VSMC priming/proliferation will then be elucidated by assessing, in explant models, the effects on clonal dynamics of pharmacologically manipulating MAPK signalling in a Myocd+/+ and Myocd+/- background. This work will give insight into the molecular mechanisms underlying disease-associated clonal VSMC expansion and enable identification of novel therapeutic targets specific to pathological VSMC proliferation.

Keywords

vascular smooth muscle cells (VSMC)

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