Generation of Zebrafish Models of Neurodegeneration
Supervisor: Dr Claire Russell (RVC)
Co-Supervisor: Professor Robert J Harvey (SoP)
Neurodegeneration is the gradual, progressive loss of the structure or function of neurones, such as that seen in Alzheimer's disease, Parkinson's disease, Huntingdon's disease or amyotrophic lateral sclerosis. However, many of the gene defects that cause neurodegeneration are still unknown and current treatments for neurodegenerative diseases are, at best, palliative. One major confounding factor is that complex interactions between neurons and supporting glial cells underlie neurodegeneration, hence screening cellular models for new drugs to treat neurodegeneration is too simplistic. This project will demonstrate the power of zebrafish as a model system for studying neurodegeneration by utilising modern genetics techniques to generate and characterise two new models of neurodegeneration that are amenable to in vivo drug screening. The use of both forward and reverse genetic approaches will provide the student with experience of two major techniques used in this field.
In the forward genetic approach, a zebrafish mutant was isolated that exhibits signs of neurodegeneration. In this project, we determine the genetic cause of this neurodegeneration. Rough genetic mapping has been performed but, further mapping and functional work is now needed to define the gene defect underlying this phenotype. In the reverse genetic approach offspring from ENU-treated fish are screened for mutations in a known gene by DNA sequencing, and then the phenotype is examined. Since defects in human mitochondrial protein kinase PINK I cause early-onset Parkinson's disease, we will screen for mutations in zebrafish PINK I gene. The phenotype caused by mutation in PINK I will be characterised.
Linkage analysis and SNP identification will be used to identify the mutation, and a variety of developmental biology techniques will be employed to characterise both mutant phenotypes.
The successful candidate will work jointly in an established research group at the Royal Veterinary College and the School of Pharmacy. This project would suit someone who is interested in neurodegeneration or in modelling disease in animals. A basic appreciation of molecular biology, genetics or developmental biology would be advantageous. The PhD studentship will be enhanced by the provision of specialized training courses available at both academic institutions. The successful candidates will have access to excellent molecular biology and zebrafish facilities.
Applicants must have or be expected to achieve at least a 2.1 degree in a relevant subject and be of home or EU status. The PhD Studentship stipend will in be in accord with BBSRC rates including a London allowance.
Key References
1. Best, JD., Alderton, WK. (2008) Zebrafish: An in vivo model for study of neurological diseases. Neuropsychiatr. Dis. Treat. 4: 567-576
2. Cooper, JD., Russell C., Mitchison, HM., (2006) Progress towards understanding disease mechanisms in small vertebrate models of neuronal ceroid lipofuscinosis. Biochim. Biophys. Acta 1762: 873-889.
3. Valente, EM., Abou-Sleiman, PM., Caputo V., Muqit, MM., Harvey, K., Gispert S., Ali, Z., Del Turco D., Bentivoglio, AR., Healy, DG., Albanese, A., Bussbaum, R, Gonzalez-Maldonado, R., Deller, T., Salvi, S., Cortelli, P., Gilks, WP., Latchman, DS., Harvey, RJ., Dallapiccola, B., Auberger, G., Wood, NW. (2004). Hereditary early-onset Parkinson's disease caused by mutations in PINK I. Science 304: 1158-1160.
4. Anichtchik, O., Diekmann, H., Fleming, A., Roach, A., Goldsmith, P., Rubinsztein, DC. (2008) Loss of PINK I function affects development and results in neurodegeneration in zebrafish. J. Neurosci. 28: 8199-8207.
Further details about the project may be obtained from:
Supervisor: Dr Claire Russell, crussell@rvc.ac.uk
http://www.rvc.ac.uk/AboutUs/Staff/crussell/Research.cfm
Co-Supervisor: Professor Robert J Harvey, robert.harvey@pharmacy.ac.uk
http://www.pharmacy.ac.uk/robert_harvey.html
Further information about PhDs at the Royal Veterinary College is available from:
http://www.rvc.ac.uk/Postgraduate/PhD/ThemesAndGroups.cfm
Application forms and details about how to apply are available from:
http://www.rvc.ac.uk/Postgraduate/Documents/PG08_forms.pdf
The Graduate School
Royal Veterinary College
Royal College Street
London
NW1 0TU
UK
Tel: 00 44 (0) 20 7468 5134
Fax: 00 44 (0) 7468 5060
E-mail: graduateschool@rvc.ac.uk
To apply, please send a completed Postgraduate Application Form (http://www.rvc.ac.uk/Postgraduate/Documents/PG08_forms.pdf) to the Registrar at the above address.
Closing date for application: 12 February 2010
