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(WIS) The role of IL1 and inflammasome activation in behavioural manifestations in neurological lysosomal disease progression

  • Full or part time
  • Application Deadline
    Friday, February 15, 2019
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Childhood dementia is a hallmark of around 2/3 of pediatric lysosomal storage disorders, together having a frequency of around 1/5500 live births. Most of these disorders are caused by the absence of a lysosomal hydrolase, responsible for degrading complex macromolecules. Depending on the substrates that accumulate as a result of the disease, neurological manifestations can be varied, but are often devastating. One common factor across many of these lysosomal diseases is neuroinflammation. Inflammation has been well characterised in murine models of GM1/GM2 gangliosides, as well as metachromatic leukodystrophy, Gaucher disease, Niemann-Pick C disease, Mucopolysaccharidosis (MPS)I, MPSIIIB and MPSIIIA. Previous studies on these models have shown an extensive inflammatory process dominated by activated microglia, astrocytosis and cell death, suggesting that inflammation might participate in neurodegeneration. Moreover, MPSIIIA mice display an abnormal phenotype, including hyperactivity, aggression and deficits in working memory, many of which are also seen in humans with this condition. Gaucher mice display similar pathological hallmarks with pronounced dementia.

We have recently identified a critical role for IL1 in disease progression and behavioural manifestations in MPSIIIA mice, and this appears to be driven by inflammasome activation (1). Similar work in Gaucher models targeting RIP kinases also implicates the inflammasome and hence IL1 secretion (2). Importantly, there are several cases of treatment involving the use of anti-inflammatories that may provide benefit to lysosomal disease progression, including the use of prednisolone in the mouse model of MPSIII, that appeared to have a significant effect on behaviour in mice, despite only being able to detect measurable cytokine changes in the periphery, and not in the brain (3). This raises the question of whether changing cytokine profiles in peripheral circulation may be sufficient to influence brain outcomes.

Our overall aim is to compare IL1 signalling across two disparate progressive neurological lysosomal storage diseases with quite different pathology and behaviours and see if we can influence behaviour via IL1 pathway blockade

A secondary aim is to determine if blockade of either or both peripheral or central brain IL1 signalling can alter brain behaviour

Entry Requirements
Applicants must be from the UK/EU and have obtained (or be about to obtain) a minimum 2:1 Bachelors honours degree or equivalent in a relevant subject area.

Funding Notes

This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Weizmann Institute of Science, as outlined on 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 Parker H, Bigger BW. The Role of Innate Immunity in Mucopolysaccharidoses. J Neurochem. 2018 Nov 19. doi: 10.1111/jnc.14632. [Epub ahead of print] Review.

2 Vitner EB, Salomon R, Farfel-Becker T, Meshcheriakova A, Ali M, Klein AD, Platt FM, Cox TM, Futerman AH. RIPK3 as a potential therapeutic target for Gaucher's disease. Nat Med. 2014 Feb;20(2):204-8. doi: 10.1038/nm.3449. Epub 2014 Jan 19.

3 Holley RJ, Ellison SM, Fil D, O'Leary C, McDermott J, Senthivel N, Langford-Smith AWW, Wilkinson FL, D'Souza Z, Parker H, Liao A, Rowlston S, Gleitz HFE, Kan SH, Dickson PI, Bigger BW. Macrophage enzyme and reduced inflammation drive brain correction of mucopolysaccharidosis IIIB by stem cell gene therapy. Brain. 2018 Jan 1;141(1):99-116. doi: 10.1093/brain/awx311.

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