Project Title: Dynamic gene regulatory networks in developing inner ear for regeneration and treatments for hearing loss
Supervisors: Dr Marta Milo and Professor Matthew Holley
Project Description
Genetic regulation in cells, organs and tissues during development provides insight into mechanisms for stimulating tissue repair and regeneration. Several known, critical transcription factors (TFs) regulate development of specific sensory cells and neurons in the mammalian auditory system. They influence important signaling pathways and modulate the activity of molecules that could be targeted for regenerative therapies for hearing loss. Techniques in computational biology applied to genomic and proteomic data can provide functional insights that yield valuable experimental predictions.
This project aims to model the dynamic interactions of a small group of TFs and their transcriptional targets in mammalian inner ear development. It will involve development of systems biology tools to model these interactions, stemming from existent approaches using differential equations and probabilistic models. Such tools will be develop not only to describe the biological system in a continuous data space, but also to enable predictions on regulatory activities that are not possible to identify with discrete measurements.
We have comprehensive gene expression datasets from knock down experiments and from temporal gene expression profiles in inner ear cell lines. We plan to complement these with gene expression profiles from single hair cells and their developmental precursors in vitro cell cultures and in animal models.
The project requires a strong undergraduate or Masters-level training in mathematical and/or computational discipline.
References:
- Milo, M. et al.
Genomic analysis of the function of the transcription factor gata3 during development of the mammalian inner ear.
PLoS One, 4(9), e7144. doi:10.1371/journal.pone.0007144 (2009). - Honkela A.. et al,
Ranking of gene regulators through differential equations and Gaussian processes Machine Learning for Signal Processing (MLSP),
2010 IEEE International Workshop - van der Wees J. et al.
Hearing loss following Gata3 haploinsufficiency is caused by cochlear disorder
Neurobiology of Disease, Vol16, Issue 1, June 2004, Pages 169–178
Contact details:
Dr Marta Milo
Email: M.Milo@sheffield.ac.uk
Web: http://www.sheffield.ac.uk/bms/research/milo
Professor Matthew Holley
Email: m.c.holley@sheffield.ac.uk