SoCoBio BBSRC doctoral training partnership Industry-led scholarship (2024)

What you get

PhD studentships cover four years of UK PhD fees and a tax free maintenance allowance (£19,237 for 2024-25) plus some research costs.

Type of award

PhD scholarship

PhD project

Project title: Development of LA1011 for high affinity binding to Hsp90 for use towards healthy ageing in patients showing Alzheimer’s symptoms.

With 50 million global cases of Alzheimer’s disease (AD) and care costs of 1 trillion UK pounds (expected to triple by 2050), there is a pressing need to slow disease progression, sustain productive lives and reduce costs. Dihydropyridines, like LA1011, are used for hypertension. However, we have shown that LA1011 eliminates neurodegeneration in an AD mouse model and identified the Hsp90-FKBP51 complex as the molecular target. Senile plaques in the brain elevate FKBP51 leading to tau pathology, a process regulated by the Hsp90-FKBP51 complex. We have determined the structure of a Hsp90-LA1011 co-complex and shown that LA1011 competes with FKBP51 for binding to Hsp90. Our results suggest that LA1011 may help to restore normal levels of FKBP51-Hsp 90 complex in AD cells, which consequently reduces tau pathology.

Our aims are straightforward and threefold. A).  A structure-based design of LA1011 to improve Hsp90 binding. B). Using biochemical, biophysical and cellular approaches, we will evaluate the importance of FKBP51 and other cochaperones (Aha1, FKBP52 etc) involved in the phosphorylation of Tau, which also compete with LA1011 for Hsp90 binding. C). LipidArt (our industrial partner) are uniquely placed to investigate whether LA1011 alters the membrane physical state, organization and effects on the lipidom and cause the co-induction effect of LA1011. This is a very relevant question since FKBP51 is involved in adipogenesis and lipid metabolism.

There is potential that full AD onset could be prevented by developing LA1011. LA1011 may be applicable to other chaperone dependant neurodegenerative diseases. LA1011 is a useful reagent for use to better understand the complex nature of the Hsp90 mechanism per se, but also in the context of a variety of other diseases (from inflammation to cancer). The project offers an excellent multidisciplinary training opportunity.

A strong interest in protein science and drug development is favourable.

References

1. The Crystal Structure of the Hsp90-LA1011 Complex and the Mechanism by Which LA1011 May Improve the Prognosis of Alzheimer's Disease.
Roe SM, Török Z, McGown A, Horváth I, Spencer J, Pázmány T, Vigh L, Prodromou C.
Biomolecules. 2023 Jun 28;13(7):1051. doi: 10.3390/biom13071051.
PMID: 37509087 Free PMC article.
 
2. Editorial: The Role of Heat Shock Proteins in Neuroprotection.
Santha M, Durham HD, Vigh L, Prodromou C.
Front Pharmacol. 2020 Aug 6;11:1227. doi: 10.3389/fphar.2020.01227. eCollection 2020.
PMID: 32848805 Free PMC article. No abstract available.
 
3. Dihydropyridines Allosterically Modulate Hsp90 Providing a Novel Mechanism for Heat Shock Protein Co-induction and Neuroprotection.
Roe MS, Wahab B, Török Z, Horváth I, Vigh L, Prodromou C.
Front Mol Biosci. 2018 Jun 7;5:51. doi: 10.3389/fmolb.2018.00051. eCollection 2018.
PMID: 29930942 Free PMC article.

4. Dihydropyridine Derivatives Modulate Heat Shock Responses and have a Neuroprotective Effect in a Transgenic Mouse Model of Alzheimer's Disease.
Kasza Á, Hunya Á, Frank Z, Fülöp F, Török Z, Balogh G, Sántha M, Bálind Á, Bernáth S, Blundell KL, Prodromou C, Horváth I, Zeiler HJ, Hooper PL, Vigh L, Penke B

Eligibility

This SoCoBio CASE studentship is open to UK applicants only.  

The Admissions team will check you application in detail but in general you count as a UK student if you are :

• a UK national who has been living in the UK or EU for the three years prior to starting your course;
• an EU national with Settled Status;
• an EU national with Pre-Settled status who has been living in the UK or the EU for 3 years prior to starting your course;
• a student with Indefinite Leave to Remain in the UK;
• an Irish National (due to a reciprocal agreement with the UK)

All other students (e.g. EU nationals moving to the UK to start their PhD) will count as Overseas students.

Ideal candidates will have a strong background in protein science and drug development. Eligible applicants will hold a 2:1 BSc in a relevant subject. 

Number of scholarships available

1 scholarship is available.

Deadline

How to apply

How to apply:

Please submit a formal application for a September 2024 start through the online admissions portal attaching a CV, degree transcripts and certificates, statement of interest and two academic references.

On the application system select Programme of Study – PhD Biochemistry. Please ensure you state the project title under funding and include the proposed supervisor’s name where required.In the “Finances/Funding” field write 'SoCoBio'

Applications are particularly welcomed from candidates with protected characteristics – e.g., from Black and other ethnic minorities – who are under-represented in postgraduate research at our institution.

International applicants are ineligible to apply

Contact us

For enquiries about the application process, please email Emma Chorley: lifesci-rec@sussex.ac.uk

For enquiries about the project, please contact supervisor: email chris.prodromou@sussex.ac.uk

For general queries about the SoCoBio programme please contact pgr-scholarships@sussex.ac.uk 

Further information on the SoCoBio website

Timetable

The deadline to apply to the University of Sussex for this scholarship is midday on 5th May 2024.

Interviews of shortlisted applicants will take place shortly after this date.