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PhD in Dementia Research - Role of a mouse ortholog of CR1 (crry) in the 3xTG model of Alzheimer’s Disease (AD)


Project Description

Several genes of the pro-inflammatory complement system, including CR1, Cr1L, Clu and C3 have been linked to AD. However, there remains a yawning gap in our understanding of how proteins derived from these genes impact risk of AD. In rodents, the closest genetic ortholog to CR1 is the broadly expressed C3 convertase regulator Crry (Cr1-related protein Y). Crry gene deletion is embryonic lethal; we rescued Crry-/- pups by inhibiting complement in pregnant dams and established a unique Crry-/- line (Ruseva et al 2009 PMID:18947875). The mice were grossly normal but displayed a “primed” microglial phenotype, Tau hyperphosphorylation and increased brain cytokine expression (Ramaglia et al 2012 PMID:22219359; Killick et al 2013 PMID:23153828). In order to explore further roles of Crry we have generated and established a 3xTG/Crry-/- colony but have not yet had resources to explore further the impact of Crry deficiency in this model. Based on our published studies, we hypothesise that deletion of Crry, by creating a pro-inflammatory state in the brain, will accelerate and exacerbate pathological changes and cognitive decline.
To test this hypothesis we will:
1. Assess disease and inflammatory markers, including complement, by IHC in brains obtained from 3xTG/Crry-/- and 3xTG/Crry+/+ controls at various ages from 3 to 18 months;
2. Assess behaviour and cognition in 3xTG/Crry-/- and 3xTG/Crry+/+ mice at different ages, applying a raft of state-of-the-art tests of cognition, emotion, anxiety, social interaction and motor function;
3. Extract RNA from micro-dissected brains (hippocampus, neo-cortex etc.) from 3xTG/Crry-/- and 3xTG/Crry+/+ mice at different ages to assess by qPCR spatial and temporal differences in expression of inflammatory (including complement) and disease-associated genes. subjected to AD targeted qPCR arrays, and confirm cellular sources of genetic hits using in situ hybridisation and/or laser microdissection.
4. Test impact on course of disease of inhibiting complement dysregulation using a complement inhibitor selected from our toolkit guided by findings in earlier aims to target the relevant pathway or effector.

Funding Notes

The funding for the studentship is provided by the UK Dementia Research Institute at Cardiff. Funding is in competition with 5 projects advertised, and an anticipation to fund 3.
Full UK/EU tuition fees
Doctoral stipend matching UK Research Council National Minimum.
Additional funding is available over the course of the programme and will cover costs such as research consumables and training.

Applicants should possess a minimum of an upper second class Honours degree, master's degree, or equivalent in a relevant subject.
Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS)

References

The duration of the PhD will be 3.5 years
In order to be considered you must submit a formal application via Cardiff University’s online application service. (To access the system click 'Apply Online' at the bottom of this advert)
There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (October 2019). This will take you to the application portal.
In order to be considered candidates must submit the following information:

• Supporting statement
• CV
• Qualification certificates
• References x 2 (references are optional but will strengthen your application)
• Proof of English language (if applicable)

In the 'Research proposal and Funding' section of your application, please specify the project title and supervisors of the project and copy the project description in the text box provided.
Please select 'No, I am not self-funding my research' when asked whether you are self-funding your research.
In the funding section, please select "I will be applying for a scholarship / grant" and specify that you are applying for advertised funding from UK DRI.

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