PhD Research Project: DiMeN Doctoral Training Partnership: Investigating the role of RNA exporter G

We are looking for highly motivated candidates to explore the role of RNA biology and processing in neurodegeneration associated with amyotrophic lateral sclerosis (ALS). ALS is a motor neuron disease characterised by progressive injury and death motor neurons in the brain and spinal cord. Emerging reports indicate that there is a strong link between mutations in genes encoding RNA-processing proteins and ALS. GLE1 is an mRNA export factor that is mutated in ALS patients. However, key questions on how mutations in GLE1 causes neurodegeneration remain unanswered. Thus, research efforts aimed at understanding how mutations in these genes cause the disease are of the utmost importance to enable therapeutic development for these devastating disorders.

The successful candidate will join a team of several postdocs and technicians and he/she will benefit from their support and expertise. The student will use/learn cell culture, basic molecular biology techniques, CRIPR/Cas9 approach, iPS -derived from ALS patients, viral vector design/production and in vivo mouse work. Gene manipulation in the cell culture model will be made using viral vectors and CRISPR Cas9 to modulate Gle1 gene. The student will learn how to administer the viral based gene therapy and how to assess the animals using behavioural testing, histological analysis of pathology and motor neuron cell numbers within the spinal cord. The student will attend several courses/workshops including Home Office course for animal experimentation. The student will analyse his/her data using the Transcription Analysis Console program (Affymetrix) prior to comparison with state-of-the-art tools that quantify uncertainty within PUMA. Dr Marta Milo, a bioinformatician from computer Sciences, who contributed to the development of the PUMA packages, will assist the student with the analysis. We support our PhD students to attend and present their research findings at national and international conferences.

The proposed work will be undertaken within the Sheffield Institute for Translational Neuroscience (SITraN: http://www.sitran.org/people), a world class environment for translational research. SITraN was specifically designed to bring together a multidisciplinary team of scientists, bioinformaticians and clinicians in order to effectively translate basic science discoveries into potential neuroprotective therapies for patients with MNDs. SITraN hosts state-of-the-art laboratories and equipment with a collaborative, multi-disciplinary environment including expertise in basic neuroscience, gene therapy, clinical neurology, neuropathology, computational biology, high throughput genomics and clinical trials methodology. The dedicated research accommodation encompasses tissue culture and gene therapy suites, facilities for live cellular imaging, confocal microscopy, laser capture microdissection, next generation sequencing, gene expression arrays and small molecule drug screening. We have an inter-faculty computational biology team embedded within SITraN that integrates and analyses our high dimensional data to iteratively develop systems models of disease.

The assembled team of supervisors has significant track record in studying the biochemistry of neurological disorders, stem cell modelling, and vector design and evaluation in pre-clinical studies using animal models of neurodegeneration. This is reflected in high impact publications in prestigious journals such as Nature, Nature Medicine and Science Translational Medicine, PNAS. For further info about the project please contact Prof Mimoun Azzouz (m.azzouz@sheffield.ac.uk) and Dr Guillaume Hautbergue (g.hautbergue@sheffield.ac.uk).

Funding Notes

DiMeN DTP studentships are funded for 3.5 years and include:

- Tax-free maintenance grant set at the UK Research Council's national rate.
- Full payment of tuition fees at the Home/EU rate.
- A Research Training Support Grant to support your research studies.

Successful Home students will receive a full studentship. EU students will be considered for a full studentship/fees only support depending on the excellence of their qualifications and their employment/residency status.

Please carefully read the instructions on eligibility and how to apply at our website and use the link on the page to submit an application: http://www.dimen.org.uk/how-to-apply/application-overview