Developing drugs for the treatment of neurodegenerative diseases

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  • Published date: December 3, 2016
    • Liverpool , United Kingdom

Ageing is arguably the major biomedical challenge of the 21st century with the incidence of age-related diseases, and neurodegenerative diseases in particular, expected to increase dramatically in the coming decades. In model organisms, the process of ageing can be retarded by both genetic manipulations and dietary interventions. Most notably, caloric restriction (CR), a reduction in calorie intake without malnutrition, extends longevity and retards age-related diseases, including neurodegeneration. Developing CR mimetics, compounds that reproduce the health and longevity benefits of CR without its side-effects, is therefore of widespread medical and commercial interest (Pharmacological Reviews (2012) 64:88-101).

In this project, we aim to identify and characterize new compounds with pro-longevity, health-promoting and neuroprotective effects that may be suitable for the treatment of neurodegenerative diseases. To achieve this, and using a network pharmacology approach applied to publicly-available drug gene expression data, the primary supervisor recently identified 11 novel candidate CR mimetic drugs. Five of these have already been tested in the roundworm C. elegans, an established model of ageing and of CR, with four significantly extending lifespan via CR-related processes (Aging Cell (2016) 15:256-266). To assess the potential of these compounds for the treatment of neurodegenerative conditions, we now aim to study the 11 new candidate CR mimetics for lifespan and healthspan effects in two worm models of neurodegenerative diseases: a dnj-14 null mutant model of adult-onset neuronal ceroid lipofuscinosis (Hum Mol Genet (2014) 23:5916) and a worm model of frontotemporal dementia expressing a human Tau mutant, parkinsonism-17 (Molecular Neurodegeneration (2015) 10:51).

Mechanisms of action will also be studied to determine whether these new compounds are working via known ageing-related pathways or if they could represent new longevity pathways. Biomarkers and candidate genes mediating CR mimetic drugs will be explored using bioinformatics analyses of the drugs’ publicly-available gene expression data, as before (PLoS Genetics (2012) 8:e1002834), and biochemical and molecular assays (qPCR, Western blot, etc.). Lastly, studies in mammalian cells will be performed to assay our compounds for potential effects relevant to humans, including neuroprotection, as previously (Molecular Neurodegeneration (2015) 10:51; Genome Biology (2015) 16:285).

There is immense current interest in repurposing drugs for the treatment of neurodegenerative conditions. We expect to identify new drugs with potential for the treatment of neurodegenerative diseases that we can then take on to further and longer studies in rodent models. Though additional studies will be necessary beyond this project, this work can culminate in the development of new treatments for neurodegenerative diseases.

This is a highly multidisciplinary and collaborative project involving not only the supervisor in Liverpool, Dr de Magalhaes, but Dr Passos in Newcastle and Dr Simons in Sheffield, in addition to local collaborators (Prof Morgan).

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.

Application Website:
http://www.dimen.org.uk/

Joao Pedro de Magalhaes
2 votes

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