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(BBSRC DTP) Selective knockdown of proinflammatory microRNAs to tackle neurodegeneration and cognitive decline: myth or reality?


Project Description

Neurodegenerative diseases (e.g. multiple and amyotrophic lateral sclerosis, Alzheimer’s and Parkinson’s diseases) have tremendous psychological, clinical and social impact, which becomes increasingly challenging in the global trend of population aging. Despite enormous technological and financial investments, not a single disease-modifying therapy has been discovered against these currently incurable diseases. Until now, the therapeutic focus was limited to only a few downstream disease hallmarks (e.g. amyloid plaques, tau protein, alpha synuclein), whereas complex pathophysiology of neurodegeneration involves multiple biological players.
Neuroinflammation has recently emerged as a new, appealing target against neurodegenerative cognitive decline [1], and a small family of proinflammatory microRNAs has been suggested as pathogenic inducers of neuroinflammation, which can trigger functional and mental impairments [2-5]. We aim here to test this hypothesis by investigating whether selective knockdown of such pathology-associated microRNAs can switch signalling pathways from ‘diseased’ to ‘normal’. Given current knockdown issues, we will apply our innovation (neuro-anti-miRs) to selectively transport, recognise and irreversibly destroy proinflammatory microRNAs. By monitoring biological responses in neurodegeneration cell models, human brain tissues and animal models of cognition upon exposure to these agents, we will investigate whether these proinflammatory microRNAs can be considered as possible therapeutic targets for development of disease-modifying treatments against neurodegeneration.
Insight into the role of neuroinflammation in the induction and progression of neurodegenerative diseases is crucial for future development of new therapeutic strategies against proinflammatory inducers. As miRNA up-regulation appears at relative early stages of the neurodegenerative process, knockdown intervention may halt disease progression before neuropathology consequences of neuroinflammation are established in diseased cells, and to stop paracrine spread into healthy tissues.
The outcomes of this research will reveal whether the identified pro-inflammatory microRNAs (alone or in combination) can be used as a therapeutic opportunity for effective targeting of neuroinflammation.
If successful, this research will provide proof-of-concept of this new therapeutic platform and accelerate translational development of neuro-anti-miR innovation into disease-modifying therapeutic discovery and pre-clinical development, towards industry investment in neurodegeneration treatment.

http://www.pharmacy.manchester.ac.uk/staff/ElenaBichenkova/
http://www.manchester.ac.uk/research/joanna.neill/
http://www.b-neuro.com
https://www.research.manchester.ac.uk/portal/federico.roncaroli.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Chen W.W, Zhang X. and Huang W.J. “Role of neuroinflammation in neurodegenerative diseases (Review).” Mol. Med. Rep. (2016) 13, 3391-3396.
2. Zhao Y., Pogue A.I. and Lukiw W.J. “MicroRNA (miRNA) signaling in the human CNS in sporadic Alzheimer’s disease (AD) - novel and unique pathological features.” Int. J. Mol. Sci. (2015) 16, 30105–30116.
3. Pogue A.I. and Lukiw W.J. “Up-regulated pro-inflammatory microRNAs (miRNAs) in Alzheimer's disease (AD) and age-related macular degeneration (AMD).” Cell Mol. Neurobiol. (2018) 38, 1021-1031.
4. Lukiw W.J. “Antagonism of NF-kB-up-regulated micro RNAs (miRNAs) in sporadic Alzheimer’s disease (AD)-anti-NF-kB vs. anti-miRNA strategies.” Front. Genet. (2013) 4, 77, 1-5.
5. Zhao Y., Jaber V.R., LeBeauf A., Sharfman N.M., Lukiw W.J. “microRNA-34a (miRNA-34a) Mediated Down-Regulation of the Post-synaptic Cytoskeletal Element SHANK3 in Sporadic Alzheimer's Disease (AD).” Front. Neurol. (2019), 10, 28, 1-7.

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