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

Exploring the contribution of divergent neuroinflammation in Alzheimer’s disease


Bristol Medical School

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

About the Project

Rationale
There is accruing evidence demonstrating an association between neuroinflammation with the onset and progression of neurodegenerative diseases, particularly Alzheimer’s disease (AD). Indeed, the inflammatory response of resident cells (microglia) and recruited inflammatory cells (monocyte/macrophages) during AD is a ripe area of research as it may help explain links between the widely known associations between inflammation-related cardiovascular risk factors and the development of AD. At the heart of most inflammatory-mediated conditions is the balance between clearance of damaged tissue (subsequent to a stroke or traumatic brain injury) and the ensuing resolution of inflammation to permit healing and restoration of function. 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 perpetuate inflammation and hamper resolution, 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 typical of chronic responses after 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 inflammatory cardiovascular diseases.

Aims and objectives
We have the knowledge and expertise to train a student to design and execute studies to investigate the association and impact of divergent macrophage subsets on the development and progression of Alzheimer’s disease. Additional aims will involve proteomic assessment and associated identification of novel non-coding RNA that are regulated in two macrophage subsets during AD. 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 AD.

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 part of their initial training and input into their projects.

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-related diseases including Alzheimer’s disease, and driving new translational therapies and identification of biomarkers for patient susceptibility.

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. Di Gregoli 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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