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Identification, characterisation and functional assessment of long non-coding RNA regulation of foam cell macrophage formation during atherosclerosis and aneurysm progression


   Bristol Medical School

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  Dr J Johnson, Dr K Di Gregoli  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Rationale
Collectively, cardiovascular pathologies including atherosclerosis, aneurysms and heart failure, account for more deaths world-wide than other diseases. Accordingly, a better understanding of the cellular and molecular mechanisms underlying these pathologies is paramount for the identification and development of both biomarkers and treatments of these diseases. The past decade has highlighted the prominent role of monocyte/macrophages in the development and progression of cardiovascular diseases, however more current research has demonstrated that it is the transformation of macrophages into lipid-laden foam-cell macrophages that drive the progression of atherosclerotic plaques and contribute to aneurysm formation in man (1). We have recently identified that foam-cell macrophages can co-exist as varying phenotypes which display an array of differing properties. Moreover, our latest findings have suggested that foam-cell macrophage subsets divergently harbour the ability to utilise non-coding RNA to alter their proteolytic potential and consequently atherosclerotic plaque and aneurysm progression (2). Furthermore, our data imply that non-coding RNA (including microRNA and long non-codingRNA) are regulated during the transformation of specific macrophage subsets into foam-cell macrophages, and during progression of atherosclerosis and aneurysms (3, 4).

Aims and objectives
The aim of this current studentship is to identify novel non-coding RNA that are regulated during foam-cell macrophage formation in numerous macrophage subsets, and robustly assess the potential of selected non-coding RNA to regulate foam-cell macrophage formation. Such an approach should result in the identification of specific novel non-coding RNA which can serve as new therapeutic targets and biomarkers for such debilitating cardiovascular diseases as atherosclerosis and aortic aneurysms.

Methods
The techniques to be used are all routine in our group and include flow cytometry, tissue culture, molecular biology, microscopy and imaging, in vitro and in vivo cell behavioural assays, as well as numerous in vivo and ex vivo models of cardiovascular disease. Detailed bioinformatics will also be deployed to mine and analyse the differential expression patterns between macrophages subsets and validate key findings in human tissue samples. In the final year of the project, the plan will be to assess the effect of modulating importantly identified non-coding RNA in models of atherosclerosis and aneurysm. As such, this project would suit a student with an interest in the understanding of human disease and inflammation. It offers the opportunity to study in an excellent research environment, in a research institute with world class facilities and resources, devoted to understanding the cellular and molecular mechanisms of cardiovascular disease, and driving new translational therapies and identification of biomarkers for patients susceptible to cardiovascular diseases.

References

1. Johnson JL and Newby AC. Macrophage heterogeneity in atherosclerotic plaques. Curr Opin Lipidol. 2009;20:370-378.

2. Di Gregoli K, Mohamad Anuar NN, Bianco R, White SJ, Newby AC, George SJ and Johnson JL. MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin. Circ Res. 2017;120:49-65.

3. Johnson JL. Elucidating the contributory role of microRNA to cardiovascular diseases (a review). Vascular Pharmacology. 2019;114:31-48.

4. Fasolo F, Di Gregoli K, Maegdefessel L and Johnson JL. Non-coding RNAs in cardiovascular cell biology and atherosclerosis. Cardiovascular Research. 2019;115:1732-1756.
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