Professor Matthew Holley
Professor of Sensory Physiology
Department of Biomedical Science
The University of Sheffield
Sheffield S10 2TN
Room: B1 218 Alfred Denny building
Telephone: +44 (0) 114 222 2374
I am primarily interested in the development and function of the mammalian inner ear with a focus on potential treatments for hearing loss. I have developed in vitro models for the differentiation of sensory hair cells and sensory nerves and use them in conjunction with microarrays to study gene networks centred on the transcription factor Gata3. I have also explored a model system for cell transplantation into the inner ear in vivo.
Activities and distinctions
Auditory neuroscience Mammalian development and regeneration
My research is focused on potential regeneration of the inner ear via cell transplantation (with Sekiya) and via activation of early developmental mechanisms. The transcription factor gata3 coordinates development of sensory cells, supporting cells and both afferent and efferent nerves. We are using various transgenic mouse lines to target gata3 expression and to explore its function in these different cell types in vivo.
I am also developing conditionally immortal cochlear cell lines carrying a reporter for gata3 that can be used for screening for genes and extrinsic factors that regulate gata3 expression. Gata3 enhances the ability of the transcription factor Atoh1 to generate new hair cells and its re-expression in adult ears could support more efficient therapeutic regeneration.
SUMOylation regulation of autophagy induced by ER stress in motor neuron disease
Co-supervisor: Dr Chun Guo
Autophagy is essential for cellular homeostasis and survival. Dysfunctional autophagy has been detected in various neurodegenerative disorders, including Alzheimer's disease (AD) and Amyotrophic lateral sclerosis (ALS)(1), and it is regarded as a suitable target for therapeutic intervention. It leads to stress in the endoplasmic reticulum (ER), which triggers the unfolded protein response (UPR) (2). The UPR has three canonical arms: IRE1α (the inositol-requiring kinase 1 α), PERK and ATF6. Abnormal activation of the IRE1α-XBP1 pathway has been detected in AD and ALS and inhibition of IRE1α activity increases cell viability in ER stress-induced degeneration (3). One function of XBP1 is to suppress neuronal autophagy and its depletion promotes autophagy, enhancing clearance of protein aggregates and ameliorating disease progression in ALS (4). Emerging evidence suggests an important role for protein SUMOylation in UPR, which influences cell survival (5). SUMOylation of XBP1 negatively regulates its function(6), so it is tempting to speculate that it can promote autophagy upon ER stress.
This exciting project will test the hypothesis that protein SUMOylation can reduce disease pathology in inherited forms of ALS by restoring autophagy via the IRE1α-XBP1 pathway. The proposed work will be conducted using a combination of techniques including molecular biology (e.g. cloning, tagging, mutagenesis), protein chemistry (e.g. GST-/His-pulldowns, co-immunoprecipitations (co-IPs), protein purification for assays of SUMOylation and protein interaction, western blotting for the detection of LC3 conversion from LC3-I to LC3-II and degradation of p62), cell culture (clonal cell lines, motor neuronal cell lines and cells derived from ALS animal models or human patients), image analysis of changes in cell/tissue morphology/histology, protein aggregation and ‘autophagic flux’ (e.g. immunocytochemistry, fluorescence and confocal microscopy) and cell viability (e.g. cytochrome c release, caspase activation, MTT, LDH assays).
For further information about this project and how to apply, see our PhD Opportunities page: