Background and significance
There remains a lack of blood-based markers that adequately reflect the inflammatory central nervous system (CNS) processes in multiple sclerosis (MS). Peripheral changes in immune cells and cytokines are seen, but it remains unclear to what extent these findings represent CNS pathology. The serum (and CSF) biomarker neurofilament light chain is approaching clinical utility, however this reflects neuronal damage and does not tell us anything about the underlying inflammatory biological processes.
Extracellular vesicles (EVs) are heterogeneous cell-derived membrane-coated vesicles that play a critical role in intercellular communication. They reflect pathophysiological processes, including changes in blood-brain barrier permeability, immunoregulation and neuroinflammation. EVs are secreted by most cell types, including neurons and astrocytes, and are detectable in different body fluids1,2. Their functions are not fully understood, but they are important in cell-to-cell communication and signalling pathways in both health and disease1-3.
Surface markers, such as L1 cell adhesion molecule (L1CAM), primarily expressed in the CNS, can be used to identify CNS-derived EVs 4,5. EVs are able to move from the brain to the systemic circulation by crossing multiple layers of the blood-brain barrier6-8. The potential of CNS-derived EVs as long term prognostic biomarkers has been shown in other diseases: EV glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) at one year following traumatic brain injury (TBI) are associated with poorer outcomes9, and EV biomarkers predict long term outcomes in HIV-related cognitive dysfunction10.
The hypotheses underlying this PhD project are that:
1. CNS-derived EVs can be detected in the peripheral blood of people with MS
2. mRNA, microRNA and proteins within CNS derived EVs differ between people with active inflammatory MS, those with disease controlled on highly active therapies, progressive disease with no evidence of inflammation, and healthy controls
3. The contents of peripherally-derived EVs originating from T and B cells differ between people with active inflammatory MS, those with controlled disease on highly active therapies, progressive disease with no evidence of inflammation, and healthy controls
EVs will be isolated from peripheral blood, and surface markers used to identify EV origin. EV quality, quantity, and protein content will be established according to EV cell origin and across groups. Selected mRNA expression levels will be established. Protein content of EVs will be assessed using Western blot and ELISA as appropriate, and compared between groups. Our pilot work has developed a protocol for the isolation of EVs from peripheral blood with good EV yield. We have also demonstrated that sufficient EVs can be obtained for in depth study of EV contents including RNA and protein. Precise mRNA expression sequences and protein markers to be studied will be informed by a thorough review of the EV and MS literature by the student. There is also the potential to capture paired CSF in some people with MS, and where possible CSF ECV content will be compared to serum.
The Trustees of The Medical College of Saint Bartholomew’s Hospital Trust (MCSBHT) have offered funding for a research studentship from the Willoughby Fund, for a clinically qualified candidate to commence in October 2022, leading to a PhD degree from The QMUL Faculty of Medicine and Dentistry.
This studentship will fund a student with a clinical qualification and GMC / GDC registration at any career stage below consultant. The Studentship will cover the successful candidate’s current clinical salary and will include PhD fees (at home fee rate) with up to £6000 pa for consumables. Further consumables / funding for travel may be available on application.
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Application Web Page: https://mysis.qmul.ac.uk/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=RFQM-WFZF-09&code2=0013