Gene therapy in a mouse model of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
To start: 1st October 2017
Award
1 fully funded 4-year PhD studentship with £20,000 p/a stipend
Project
Amyotrophic Lateral Sclerosis (ALS, also known as motor neuron disease) and fronto-temporal dementia (FTD) are fatal neurodegenerative diseases for which no effective therapies currently exist. ALS causes muscular paralysis due to progressive motor neuron degeneration and FTD causes progressive changes to personality, behaviour and language. Despite a large number of underlying genetic defects 95% of ALS and tau-negative FTD patients share a common pathology at post-mortem revealing cytoplasmic inclusions containing TDP-43 protein (Neumann et al., 2006). TDP-43 is a DNA and RNA binding protein that plays a major role in regulating the transcription, editing, transport and translation of ~6,000 different RNA transcripts. We have shown that mutant and wild-type forms of TDP-43 protein can misfold, aggregate and become highly neurotoxic in a range of cellular and animal models (Sreedharan 2008; Scotter 2013 and Mitchell 2015). This project aims to explore the potential of gene therapies designed to remove TDP-43 aggregates and prevent neurodegeneration.
We have recently discovered that several members of a family of specialised chaperones, called heat shock proteins (HSPs), are able to refold and enhance the clearance of aggregated TDP-43 (Chen 2016). We showed that expression of Heat Shock Factor 1 (HSF1), the master transcription factor driving the chaperone response, is able to dramatically clear TDP-43 aggregates and rescue cultured cells. Interestingly the levels of HSF1 and HSPs are significantly reduced in the spinal cord tissues of both ALS patients and a TDP-43 transgenic mouse, suggesting the loss of this pathway is disease-critical (Chen et al., 2016).
The first potential gene therapy we plan to test in our TDP-43 transgenic mouse model of ALS and FTD is HSF1 to determine whether we can drive HSP-mediated rescue of TDP-43 aggregation and toxicity (Mitchell 2015). A dominantly active form of HSF1(+), will be delivered to mouse brain and spinal cord tissues by injection of the adeno-associated virus AAV in pre-symptomatic and symptomatic TDP-43 transgenic mice. The therapeutic effect of HSF1(+) will be evaluated in live animals by measuring motor phenotypes and cognitive tasks and survival. In brain and spinal cord tissues will measure the heat shock protein levels achieved following HSF1 expression and the clearance of aggregated TDP-43 from neural tissues. This study will provide principle foundation on the potential of HSF1 as gene therapy for ALS and other neurodegenerative diseases associated with protein aggregation. Other gene therapy targets and approaches will be explored during the project.
The student will join one of the world’s leading ALS and FTD laboratories in the newly built Wohl Institute where they will acquire cutting-edge expertise in many molecular biology and gene therapy techniques including the generation of viral vectors, microsurgery, behavioural phenotyping, western blotting and immunocytochemistry using state-of-the-art microscopy and image analysis.
For more details/informal enquiries, please contact Dr. Han-Jou Chen
Supervisors
Professor Christopher E. Shaw, Dr Han-Jou Chen and Dr Jacqueline C Mitchell
Entry requirements
Applicants should have (or be expected to obtain) a 2:1 or 1st class honours degree in a subject relevant to the proposed project. If applicants already possess (or expect to obtain) a research-based MSc degree, a merit or distinction level is required.
Award type and eligibility
The award covers PhD tuition fees and a competitive stipend for UK/EU nationals
How to apply
Applicants must complete and submit an online admissions application, via the admissions portal by midnight (23:59 GMT), Sunday 28th May 2017.
On the ‘Choosing a programme’ page, please select ‘Research degrees’ and enter the keyword Clinical Neuroscience.
In your application, you will be asked to include:
- Academic Transcripts – where applicable, academic transcripts must be submitted with the online admissions application
- Details of your qualifications (you will need to attach copies)
- Details of previous employment
- A personal statement describing your interests and why you wish to apply for this project. Please include this as an attachment rather than using the text box.
- Academic References – all admissions applications require two supporting references. If the applicant is relying on his/her referees to submit references directly to the College after he/she has submitted his/her admissions application, then the applicant must ensure that their chosen referees are made aware of the funding deadline.
In the Funding section, please tick box 5 and include the following reference: HJC-HSF1-2017
Please note there is no need to complete the Research Proposal section in your application as the project has already been set.
You are welcome to email Dr. Han-Jou Chen for more information regarding the project and studentship.
If you have any queries regarding the application process, please contact the Postgraduate Research Administrator.
References must be received by the deadline for the applicant to be eligible.
Only shortlisted applicants will be contacted.
Closing Date: Sunday 28th May 2017 (23:59 GMT)
Interviews: TBC - Mid-June 2017.
Further Information
About the IoPPN
Studying at the IoPPN
Research degrees at the IoPPN