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Understanding the mechanisms of AAV9 crossing of brain-blood barrier

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  • Full or part time
    Prof M Azzouz
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Gene therapy allows unrivalled development of efficient treatments tailored to individual patients. Currently, adeno-associated virus serotype 9 (AAV) is the gold standard for gene therapeutics of neurodegenerative diseases. Remarkable efficacy safety were reported in recent pre-clinical and clinical trials providing great optimism for utility as a therapeutic strategy in man. AAV9 has an enhanced ability to cross brain-blood barrier (BBB), the mechanism, however, is currently unknown. As part of our previous work, we have been identifying BBB targets for AAV9 entry using siRNA knock-down revealing candidate viral receptors.

The objective of this studentship is to further develop and validate the identified targets. The student will use four main approaches to validate previously identified target receptors and cargo proteins involved in AAV endothelial transcytosis: (1) AAV internalization and/or transcytosis following CRISPR knockdown of key receptors. This will be achieved in human iPSC models with inducible CRISPR/Cas9; (2) Flag-tag fusion proteins of key identified targets and IP pulldown experiments will be used to confirm the interaction between the target and AAV; (3) Proteomics analysis will be performed on isolated endosomes; (4) in vivo biodistribution.

Funding Notes

Funding:
Innovative Medicine Initiative (IMI) Award

Funding covers tuition fees and stipend of:
Year 1: £15,296
Year 2: £15,755
Year 3: £16,228

Entry Requirements:
Candidates must have a first or upper second class honors degree or significant research experience.

Enquiries:
Interested candidates should in the first instance contact (Professor Mimoun Azzouz, telephone: +44 (0)114 222 2238 & email: [Email Address Removed])

How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select "Neuroscience" as the department.

References

Iannitti T, et al. Molecular Therapy - Nucleic Acids, 12, pp. 75-88 (2018)
Chandran JS et al. Scientific Reports 7(1):14766. (2017)
Valori F.C et al. Science Translational Medicine. 2, 35ra42 (2010)
Walker C, et al., Nature Neuroscience 20(9):1225-1235 (2017)



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