Supervisor:   Dr Patrick LewisDr Claire Thornton

Department:  Comparative Biomedical Sciences

Project Detail:

Mutations in Leucine Rich Repeat Kinase 2 (LRRK2) and Tank Binding Kinase 1 (TBK1) cause Mendelian forms of Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS)/Frontotemporal dementia (FTD) respectively. These kinases have been linked together by previous research revealing a potential direct phosphorylation of LRRK2 by TBK1, and have both been implicated in the regulation of cell death and macroautophagy. LRRK2 is a member of the Receptor Interacting Protein Kinase (RIPK) family of kinases, and a recently published study has reported that TBK1 can directly phosphorylate RIPK1, a kinase that has a key role in the regulation of cell death pathways in the cell. Importantly, all three of these kinases are the target of ongoing drug development and clinical trials for neurodegenerative diseases, highlighting the need to gain further insight the pathways that potentially connect their cellular activities. This also provides access to an exceptional range of commercially available tool compounds and antibody-based markers for enzymatic activity, facilitating a detailed pharmacological characterization of their cellular roles. The goal of this project will be to investigate the interplay between these three kinases, expanding our understanding of their roles in the etiology and pathogenesis of neurodegeneration.

Objective 1 – carry out a detailed characterization of the relationship between LRRK2, TBK1 and RIPK1 using a panel of commercially available small molecule inhibitors of the kinase activity of each of these proteins.

Objective 2 – test how inhibition of each of these kinases impacts on cytotoxic pathways within the cell

 

References

  1. Price A, Manzoni C, Cookson MR, Lewis PA. The LRRK2 signalling system. Cell Tissue Res. 2018 Jul;373(1):39-50. doi: 10.1007/s00441-017-2759-9. Epub 2018 Jan 8. PMID: 29308544; PMCID: PMC6015615.

  2. Manzoni C, Mamais A, Roosen DA, Dihanich S, Soutar MP, Plun-Favreau H, Bandopadhyay R, Hardy J, Tooze SA, Cookson MR, Lewis PA. mTOR independent regulation of macroautophagy by Leucine Rich Repeat Kinase 2 via Beclin-1. Sci Rep. 2016 Oct 12;6:35106. doi: 10.1038/srep35106. PMID: 27731364; PMCID: PMC5059726.

  3. Martens S, Hofmans S, Declercq W, Augustyns K, Vandenabeele P. Inhibitors Targeting RIPK1/RIPK3: Old and New Drugs. Trends Pharmacol Sci. 2020 Mar;41(3):209-224. doi: 10.1016/j.tips.2020.01.002. Epub 2020 Feb 5. PMID: 32035657.

  

Requirements

Applicants should have a first or second class university honours degree in biological sciences, a veterinary or medical degree.

This is a full-time (12 month) project commencing in October 2020, based at RVC's Camden campus.

 

Funding

The MRes student will be expected to cover £5,000 of the project costs, course fees and their living expenses.

For further information on funding options please see the page below:

https://www.rvc.ac.uk/study/postgraduate/mres#32-postgraduate-master-s-loan-2019-20

We welcome informal enquiries - these should be directed to plewis@rvc.ac.uk

    

How to Apply

For more information on the application process and English Language requirements see How to Apply.

Deadline: 18/05/2020

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