Applications are invited for four year Postgraduate studentships, supported by the Midlands Integrative Biosciences Training Partnership (MIBTP) and Biotechnology and Biological Sciences Research Council (BBSRC). Up to 2 studentships are available.
The studentships are available to start in October 2021.
Background to the Studentship
MIBTP scholars join a programme of skills training in year 1. Applicants are required to select an area of study (https://warwick.ac.uk/fac/cross_fac/mibtp/areas_of_research/), but may join the programme with or without selecting a preferred project. The skills training programme includes short rotation projects and students are able to choose a PhD project once they have experienced these differing research environments.
Potential PhD projects are provided to give applicants an idea of the breadth of research within MIBTP and specific research topics at Aston University. You can browse the other projects available here (URL: https://www.findaphd.com/phds/program/midlands-integrative-biosciences-training-partnership-mibtp-funded-phd-studentships/?i369p1045). Additional projects will become available during Year 1 and students can work with potential supervisors during their first year to develop a particular project.
Project Outline
Mutations in the gene encoding DJ-1 are associated with autosomal recessive forms of Parkinson’s disease (PD). DJ-1 plays a role in protection from oxidative stress, but how it functions as an “upstream” oxidative stress sensor is still unclear. Stress granules (SGs) are cytoplasmic aggregates that represent the morphological consequence of an mRNA triage process triggered by environmental stresses (Anderson and Kedersha, 2008). These structures are characterized by the presence of the translationally silent 48S preinitiation complex (mRNA transcripts, 40S ribosomal proteins, eIF3, eIF4A, eIF4B, eIF4G and eIF4E and PABP-1) and represent the physical place within the cytoplasm of stressed cells where the fate of mRNA transcripts is decided. In our recently published article in Molecular Neurobiology (Repici et al., 2019) we show that DJ-1 interacts with several SG components in mammalian cells and localizes to SGs upon induction of stress. Our results indicate a possible link between DJ-1 and RNA dynamics which may be relevant for PD pathogenesis and fits within the emerging area of RNA metabolism and neurodegenerative diseases.
This project aims at further investigating the role of DJ-1 in RNA dynamics, to elucidate how DJ-1 interactions with mRNAs changes in pathological versus physiological conditions. This will be achieved by a) exploring the DJ-1/RNA interactome and its role in translation, b) studying the compartmentalization of DJ-1 within stress granules and c) determining the mRNA populations targeted by DJ-1 to SGs. Ultimately, such analyses will further elucidate how DJ-1 loss of function leads to PD.
The project will involve:
• Genomic approach to study the RNA populations in neuronal cells that interact with DJ-1 in different stress conditions. The mouse dopaminergic neuronal SN4741 cell line will be exposed to hyperosmotic shock, oxidative stress or MPP+, and will be lysed in polysome lysis buffer. RNAs interacting with DJ-1 will be purified by co-immunoprecipitation as in Repici et al. 2109, and RNA sequencing will be carried out. Gene ontology and related bioinformatics approaches will be employed to identify functional groups arising from the various stimuli, which will inform the signalling pathways regulated by DJ-1.
• Use of U-2 OS cells expressing a GFP-G3BP1 fusion protein to isolate SG cores after different type of stress (hyperosmotic shock, oxidative stress, MPP+). Immunoblotting will be performed on the SG cores to look for total DJ-1, as well as oxidized forms of DJ-1. This will clarify whether DJ-1 acts as an RNA shuttle protein in the outer shell of SGs or as a core SG component. Mass spectrometry will be used for the analysis of SG components to identify DJ-1 oxidation state and post translational modifications.
• RNA in situ hybridization of the DJ-1 interacting mRNAs in stress conditions will be performed using using the RNAScope Multiplex Assay and combined with immunofluorescence for SG markers in relevant cells. This work will clarify whether candidate mRNAs being regulated by DJ-1 are being sequestered in SGs during stress conditions.
Person Specification
The successful applicant should have been awarded, or expect to achieve, a Masters degree in a relevant subject with a 60% or higher weighted average, and/or a First or Upper Second Class Honours degree (or an equivalent qualification from an overseas institution) in a relevant subject. Full entry requirements for Aston University can be found on our website (URL: https://www.aston.ac.uk/study/courses/phd-life-and-health-sciences).
Full entry requirements for MIBTP can be found on their website (URL: https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/#Eligibility).
Contact information
For further information on the advertised project, contact Dr. Mariaelena Repici [Email Address Removed]
Submitting an application
Details of how to apply for the studentship can be found here (URL: https://jobs.aston.ac.uk/Vacancy.aspx?ref=R210131).
If you require further information about the application process contact the Postgraduate Admissions team [Email Address Removed]
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