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Engineering and Physical Sciences Research Council Featured PhD Programmes
FindA University Ltd Featured PhD Programmes

Assessing neuroinflammation and vascular dementia in association with atherosclerosis and aneurysm risk


Bristol Medical School

, Applications accepted all year round Self-Funded PhD Students Only

About the Project

Rationale
There is now substantial data demonstrating an association between high morbidity and mortality cardiovascular diseases (such as atherosclerosis and aortic aneurysms) with the onset of neurodegenerative diseases, particularly vascular dementia. Accordingly, and in alliance with an increase in population age, vascular dementia has become a prominent area of research. One common process that links atherosclerosis, aneurysms, and vascular dementia is inflammation, particularly the involvement of the innate immune response characterised by monocyte/macrophage accumulation. Recent novel findings, including our own research, have identified that monocyte/macrophages can co-exist as varying phenotypes which display an array of differing properties. Specifically, we have characterised a unique monocyte/macrophage subset which can direct and promote a pro-inflammatory response, typical of progressing cardiovascular diseases. Moreover, our latest findings have suggested that monocyte/macrophage subsets divergently harbour the ability to utilise non-coding RNA to alter their behaviour and dictate the persistent inflammation and inability to resolve such responses during vascular injury. Furthermore, our data imply that non-coding RNA (including microRNA and long non-codingRNA) are regulated during the maturation of specific macrophage subsets, and during progression of cardiovascular diseases.

Aims and objectives
The aim of this current studentship is to assess the association of divergent macrophage subsets with the development and progression of vascular dementia, and the impact of pre-existing cardiovascular diseases. Additional aims will involve proteomic assessment and associated identification of novel non-coding RNA that are regulated in numerous macrophage subsets during vascular dementia. Such approaches should result in the identification of specific novel non-coding RNA and/or soluble proteins which can serve as new therapeutic targets and/or biomarkers for early detection of vascular dementia and correlation with other cardiovascular diseases such as atherosclerosis and aortic aneurysms.

Methods
There are multiple potential projects available in this topic area and where following consultation we would design a suite of methodological approaches to investigate the agreed research questions. Ordinarily most studies commence with foundation experiments (using molecular genetic, biochemical, immunohistochemical and/or histological approaches) in carefully selected post-mortem brain tissue from diseased and non-diseased persons. These are then usually extended to include complementary studies designed and executed in other laboratory experimental systems (in vitro or cell-culture based), ex vivo (in disease models or more human tissue sources) or in vivo in small pre-clinical trials (time and resources permitting). Projects are intentionally not prescriptive at this stage as we seek to give PhD students the opportunity to develop and design projects with us from the outset as parts of their initial training and input into their projects.

All techniques to be used are routine in our laboratory. 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 diseases including vascular dementia, and driving new translational therapies and identification of biomarkers for patients susceptible to such 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.

5.DiGregoli K, Somerville M, Bianco R, Thomas AC, Frankow A, Newby AC, George SJ, Jackson CL, Johnson JL. Galectin-3 identifies a subset of macrophages with a potential beneficial role in atherosclerosis. Arterioscler Thromb Vasc Biol. 2020;40:1491–1509.

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