The Role of Retrograde Mitochondrial Signalling and Epigenetic Reprogramming in Glial Toxicity and Neuroinflammation in Progressive Multiple Sclerosis

About the project

About the Project Summary This project will investigate the interplay between mitochondrial dysfunction, retrograde signalling, epigenetic modifications, and glial cell toxicity in P-MS, building upon the finding’s recent papers from the lab 1, 2, 23 . The focus will be on understanding how mitochondrial stress triggers epigenetic changes that drive the transition of astrocytes to a dysfunctional disease-associated radial glia-like (DARG) phenotype, contributing to the chronic neuroinflammation of P-MS 3 . The candidate would gain expertise in various "-omics" technologies, gene editing, molecular biology, cell culture, and potentially in vivo techniques. The study will utilize iNSCs derived from P-MS patients and controls, as well as post-mortem brain samples or access to publicly available human datasets (eg snRNAseq and ST) 1, 2, 4-8 . Project Aims Methodologies will include: 1. Mitochondrial stress induction and manipulation: Using various stimuli to induce mitochondrial stress in iNSCs 23 and assess downstream signalling and mt-dsRNA release. 2. Retrograde signalling analysis 9, 10 : Studying the pathways by which mitochondrial signals (including mt-dsRNA) 23 communicate with the nucleus and influence gene expression and epigenetic modifications 11 (e.g., using RNA-seq, ATAC-seq, ChIP-seq, MeDIP-seq). 3. Epigenomic profiling: High-resolution mapping of DNA methylation, histone modifications, and chromatin accessibility changes in iNSCs and DARGs, with a particular focus on genes and pathways related to inflammation and senescence 2 . 4. Functional studies: Using CRISPR-Cas9 gene editing and other techniques to manipulate key genes involved in retrograde signalling and epigenetic changes. 5. In vivo validation: Prioritize thorough in vitro work using iNSCs to establish a robust mechanistic understanding of the processes before attempting in vivo validation with brain organoids (available in the lab) 12, 13 . Consider in utero xenotransplantation 14 only as a subsequent project if substantial in vitro progress justifies the additional challenges (eg if feasible, depending on project timeline and resources). The overall goal is to establish a comprehensive model of how mitochondrial stress, retrograde signalling, and epigenetic alterations 15, 22 work together to drive the transition to DARGs and to explore potential therapeutic targets to prevent or reverse this process. How to Apply; If you are interested in this project, please go to the University pages and apply via the online portal; PhD https://www.postgraduate.study.cam.ac.uk/courses/directory/cvcnpdpcn/apply Research MPhil https://www.postgraduate.study.cam.ac.uk/courses/directory/cvcnmpmds/apply

Research areas