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  Drug discovery for amyloid plaques based neurodegenerative disorders (ref: SF22/HLS/APP/MEERA)


   Faculty of Health and Life Sciences

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  Dr M Soundararajan  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Alzheimer’s disease (AD) followed by Parkinson’s Disease (PD) are the two most prominent causes of dementia that poses a huge health burden in an increasingly ageing population worldwide. The neurodegenerative diseases of AD and PD that result from genetic, environmental, and epigenetic factors is the major cause of poor quality of lives in over 65s and represent a huge economic burden for healthcare systems. While familial diseases accounting for 10% of the affected individuals may be associated with gene mutations, the precise reason for onset, and acceleration of the sporadic form of these neurodegenerative diseases (ND) are yet to be fully understood. The sporadic form of the neurodegenerative disorders that occurs in around 90% of the patients are influenced by genetic, environmental and other unknown factors. The hallmarks feature of these neurodegenerative diseases include formation of senile plaques, neurofibrillary tangles (NFT), hyperphosphorylated tau, aggregated α-synuclein and Lewy bodies in the human brain. Recently emerging compelling evidence connect these hallmark features to microbes that invade us during infection as well as naturally residing human microbiome. Several bacterial species in the enteric system secrete amyloids as part of their biofilms to enhance survival and propagation in the host. These microbial amyloidogenic entities that closely resemble human amyloids structurally interact with each other and trigger increased amyloid deposition and uncontrolled polymerisation of fibrils that result in NFT and plaques resulting in neurodegeneration. There are several drug development programs focussed on these NDs but there is no cure yet. Currently available therapeutics unfortunately only offer symptomatic temporary relief. Development of drugs that mounts a unilateral attack on host Aβ disintegration, NFTs or interference with Aβ aggregation using small molecule inhibitors has not been successful. Therefore, the focus of this investigation will be to develop novel hit and lead molecules that will combinatorially act on Aβ formation, toxicity in addition to amyloid contained in the microbial biofilms that get transported via blood and nerves to the brain resulting in senile plaques

The project aims include

a)     Validation of novel natural compounds that can disrupt or dissociate human and bacterial amyloid biofilms that enhance the propagation of human amyloid depositions.

b)     Targeting specific human and microbial kinases involved in hyperphosphorylation of tau and neurofibrillary tangles

c)     Evaluating inhibitors to stop or reverse ND hallmark changes using cell line models and organoid systems.

d)     Finally, determine the molecular and signalling pathways effected by the compounds using “omics” methodologies such as genomics and proteomics.

The project will enable the candidate to acquire research and technical skills in molecular biology, biochemistry, mammalian cell culture, assay development, genomics, proteomics and scientific communication.

We are seeking a candidate who is enthusiastic and self-motivated with a background in Biosciences, Bioengineering, Computational biology or Chemistry. This research project will suit a candidate who can learn quick and willing to undertake lab-based research project.

Eligibility and How to Apply:

Please note eligibility requirement:

•      Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non- UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above)

•      Appropriate IELTS score, if required

For further details of how to apply, entry requirements and the application form, see https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/

 

Please note: All applications must include a covering letter (up to 1000 words maximum) including why you are interested in this PhD, a summary of the relevant experience you can bring to this project and of your understanding of this subject area with relevant references (beyond the information already provided in the advert). Applications that do not include the advert reference (e.g. SF22/…) will not be considered.

 

Deadline for applications: Ongoing

Start Date: 1st October and 1st March are the standard cohort start dates each year.

Northumbria University is committed to creating an inclusive culture where we take pride in, and value, the diversity of our doctoral students. We encourage and welcome applications from all members of the community. The University hold a bronze Athena Swan award in recognition of our commitment to advancing gender equality, we are a Disability Confident Employer, a member of the Race Equality Charter and are participating in the Stonewall Diversity Champion Programme. We also hold the HR Excellence in Research award for implementing the concordat supporting the career development of researchers.

Informal enquiries to: Dr Meera Soundararajan

 Email: [Email Address Removed]

Biological Sciences (4)

Funding Notes

This project is fully self-funded and available to applicants worldwide. Tuition fees will depend on the running cost of the individual project, in line with University fee bands found at https://www.northumbria.ac.uk/study-at-northumbria/fees-funding/. The fee will be discussed and agreed at interview stage.
Please note: to be classed as a Home student, candidates must meet the following criteria:
Be a UK National (meeting residency requirements), or
have settled status, or
have pre-settled status (meeting residency requirements), or
have indefinite leave to remain or enter.
If a candidate does not meet the criteria above, they would be classed as an International student.

References

Understanding Miro GTPases: Implications in the Treatment of Neurodegenerative Disorders.
Laura Kay, Ilse S Pienaar , Ruwini Cooray, Gary Black , Meera Soundararajan. 2018 Mol Neurobiol 55(9):7352-7365
Novel 1-hydroxypyridin-2-one metal chelators prevent and rescue ubiquitin proteasomal-related neuronal injury in an in vitro model of Parkinson's disease. Lewis FW, Fairooz S, Elson JL, Hubscher-Bruder V, Brandel J, Soundararajan M, Smith D, Dexter DT, Tétard D, Pienaar IS. 2020 Arch Toxicol. Mar;94(3):813-831.
Proteomics and bioinformatics analyses identify novel cellular roles outside mitochondrial function for human miro GTPases. Kay LJ, Sangal V, Black GW, Soundararajan M. 2019 Mol Cell Biochem. Jan;451(1-2):21-35.

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