Additional supervisor: Dr Claudia Kutter [Karolinska Institutet]
Background
Multiple sclerosis (MS) is a chronic autoimmune disease without known cure that affects the central nervous system and is the primary cause of non-traumatic disability in young adults. In MS, demyelination affecting nerves in the brain and spinal cord is driven by dysregulated immune cells. Risk factors for developing MS include viral infection, genetic and environmental factors including reduced sun exposure [1]. MS incidence varies by geographical location with higher incidence rates at greater distance from the equator. Scotland has amongst the highest rates of MS in the world with 1 in 500 people affected. Sunlight results in production of vitamin D (vitD) by the body. VitD acts as immunomodulator that binds the nuclear vitD receptor (VDR) and controls gene transcription of innate and adaptive immune cells. A correlation exists between vitD deficiency and MS development/progression, yet findings to date suggest that vitD supplementation does not conclusively impact MS progression. Rather, sunlight drives vitD-dependent and -independent immune pathways and both appear to be important in MS [2].
Neutrophils are short-lived, highly abundant circulating immune cells in humans that are key to host damage in autoimmunity [3]. Neutrophils infiltrate active lesions in MS and in its mouse model, EAE [e.g. 4]. Inhibiting neutrophil infiltration into new lesions reduced disease onset in EAE. Genetic experiments with mice have identified that neutrophils contribute to neurodegeneration in EAE, for example by employing neutrophil extracellular traps that weaken the brain blood barrier and drive demyelination and also by undergoing changes that permit them to engage in cross-talk with B and T cells [4 and others]. Neutrophils isolated from MS patients are characterized by changes in their proteome, suggesting that functional and transcriptional changes in neutrophils occur also in MS. Neutrophils express VDR, and reports in the literature suggest vitD to have immunomodulatory, anti-inflammatory functions. However, neutrophils were only recently recognized as transcriptionally active, and their vitD (or indeed sunlight)-induced transcriptional changes have not yet been analysed in any depth. This contrasts with monocytes, B and T cells, which have already been shown to be regulated transcriptioinally by sunlight in a vitD-dependent and -independent fashion [2; unpublished results, Weller laboratory].
This project will address the hypothesis that neutrophils are important drivers of inflammation in MS, and that vitD/sunlight exerts important immunomodulatory functions by regulating neutrophil transcription, and thereby also MS development and progression.
Aims
This project will
Training outcomes
This project will combine experimentation and data analysis. To examine how vitD and sunlight regulate transcription, neutrophils will be isolated from healthy Scottish volunteers in winter when sunlight is insufficient to generate vitD. Blood will be taken on three occasions (at baseline; after 4 weeks vitD supplement; after 4 weeks controlled sunbed, allowing us to differentiate between changes induced by vitD and any other effects of sunlight). Analysis of the neutrophil (bulk) transcriptome under the three conditions will be performed. In parallel, MS patient neutrophils will be analysed, comparing their transcriptome with that of neutrophils from healthy controls, complemented by some analysis of serum to ascertain vitD, and markers of neutrophil activation/inflammation. Once transcriptome analysis has been completed, experiments will be designed to validate findings (e.g., validating RNA expression on a protein level). In this way, this project provide in-depth training of a PhD student, generate novel insights and build a platform for potential future improved treatment of MS patients.
Q&A Session
If you have any questions regarding this project, you are invited to attend a Q&A session hosted by the Supervisor(s) on Tuesday 2nd December at 10.30am GMT via Microsoft Teams. Click here to join the meeting.
About the Programme
This MRC programme is a joint programme delivered between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection and will be awarded upon successful completion of your PhD will be awarded by your lead institution.
All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with the University of Glasgow. Please note, you must apply to a specific project as advertised on the Precision Medicine webpages and FindAPhD. Additional information on the application process is available at the link below:
https://www.ed.ac.uk/usher/precision-medicine/app-process-eligibility-criteria
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