NPIF Innovation Fellowships

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

This research project focuses on linking gene expression changes in human subjects with objectively measurable natural behaviour (ehtomics) in humans. We focus on Friedreich’s ataxia (FRDA), a currently incurable and devastating disease caused by the expansion of a repetitive DNA GAA repeat within the non-coding region of the Frataxin gene that leads to the gene becoming compacted by heterochromatinisation, inaccessible and repressed (1, 2). We and others have recently shown that this compacted state can be overcome by deacetylase inhibitors which are therefore a potential disease- modifying therapy (3, 4). It is FXN deficiency that is thought to render the cells sensitive to oxidative damage and impairs mitochondrial function. We will model how changes in frataxin gene expression and chromatin structure translate into gene expression changes (RNAseq) at the genome-wide level in disease-relevant cell types and thereby identify the molecular pathways which lead to the disease phenotype and correlate these with identifiable measurements of changes in behaviour. FXN deficiency in FRDA leads to poorer proprioception, motor control and fine motor coordination that are identifiable and measureable so far only through coarse grained clinical standard measures. The overall plan is to gain insight into FRDA pathogenesis by tracking disease progression and correlating gene expression changes with disease severity longitudinally. This project has been seeded by the development of a novel behavioural biomarker using FRDA patients and controls (Faisal, Festenstein MS in prep 2017; 5,6) and will allow us to identify causal molecular pathways that are directly relevant to the patient