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EASTBIO Influence of systemic inflammation on neurodegeneration during CNS prion disease


Project Description

Royal (Dick) School of Veterinary Studies / The Roslin Institute

We have an exciting opportunity for an enthusiastic Ph.D. student with an appropriate immunology or neuroscience degree to study the influence of systemic inflammation on glial cell responses and the development of neuropathology during CNS prion disease.
Prion diseases such as Creutzfeldt-Jakob disease (CJD) in humans, BSE in cattle and scrapie in sheep, are chronic, fatal, neurodegenerative diseases to which there are no cures [1]. Pathogen infection and systemic inflammation can each influence the progression of some neurodegenerative disorders in the CNS. For example, systemic inflammation may increase cognitive decline in Alzheimer’s disease patients, and gastrointestinal infections may also increase the risk of Parkinson’s disease and exacerbate the neuronal damage caused by stroke. Our recent data also suggest that inflammatory mediators produced in response to co-infections with gastrointestinal pathogens similarly enhance the progression of CNS prion disease. Prion infection in the CNS is accompanied by extensive activation of the glial cells known as astrocytes [2]. However little is known of the precise influence that these glial cells have on the development of neurodegeneration during CNS prion disease. The astrocytes in the brain provide homeostatic support to neurons in the steady state, but undergo reactive astrocytosis following brain injury and during neurodegenerative diseases such prion diseases. Whether the astrocytes play a role in the development of, or protection from, the neurodegeneration during prion disease is uncertain, and addressing this knowledge gap will be a major focus of this project. Reactive astrocytes can be divided into two main subclasses based on their transcriptional and functional characteristics. The A1 subclass of reactive astrocytes are considered to be neurotoxic, whereas the A2 astrocytes express neurotrophic factors and are considered to be neuroprotective [3]. The A1 astrocytes can be induced in the brain following exposure to stimuli such as bacterial LPS or pro-inflammatory cytokines. This raises the possibility that exposure to systemic inflammatory mediators that manipulate the activation phenotype of astrocytes may similarly modulate the progression of CNS prion disease. Therefore, this project will also test the hypothesis that the effects of systemic inflammation on astrocyte function in the brain exacerbate the development of neuropathology during CNS prion disease. A thorough understanding of the cellular and molecular factors that can influence the progression of the pre-clinical phase will identify those that can enhance the risk of developing clinical prion disease.

Throughout this project novel in vivo and in vitro (cell culture systems) models will be used to address the project’s main aims. This studentship will therefore provide excellent training opportunities in state-of-the-art immunology, neurobiology, bioimaging, cell biology and transcriptomics techniques.

Eligibility:
All candidates should have or expect to have a minimum of an appropriate upper 2nd class degree. To qualify for full funding students must be UK or EU citizens who have been resident in the UK for 3 years prior to commencement.

Funding Notes

Completed application form along with your supporting documents should be sent to our PGR student team at

References:
Please send the reference request form to two referees. Completed forms for University of Edinburgh, Royal (Dick) School of Veterinary Studies and the Roslin Institute project should be returned to by the closing date: 5th January 2020.

It is your responsibility to ensure that references are provided by the specified deadline.
Download application and reference forms via:
View Website

References

1-Mabbott NA (2017) How do PrPSc prions spread between host species, and within hosts? Pathogens 6:e60; doi:10.3390/pathogens6040060.
2-Bradford BM, Wijaya CAW & Mabbott NA (2019) Discrimination of prion strain targeting in the central nervous system via reactive astrocyte heterogeneity in CD44 expression. Frontiers in Cellular Neuroscience 13:411; doi:10.3389/fncel.2019.00411
3-Liddelow SA et al. (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541: 481-487; doi:10.1038/nature21029

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