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Analysis of the neurobiological functions of Trafficking protein particle complex subunit 9 (Trappc9), which is associated with microcephaly and cognitive deficits in a knock-out mouse model


Faculty of Health and Life Science

Dr A Plagge , Dr Fiona LeBeau Friday, January 22, 2021 Competition Funded PhD Project (Students Worldwide)
Liverpool United Kingdom Biochemistry Cell Biology Developmental Biology Genetics Molecular Biology Neuroscience

About the Project

In this PhD project, you will investigate the neurobiological functions of the Trappc9 protein using a knock-out mouse line that we have generated recently. Trappc9 knock-out mice show reduced brain size (secondary microcephaly starting in juveniles), behavioural deficits and increased body weight, similar to human patients with TRAPPC9 mutations. Trappc9 is a specific subunit of the intracellular trafficking protein particle TrappII. It has been shown that cells deficient for this protein form unusually large lipid droplets, but neurons have not yet been investigated. This project will follow up on our initial data from neuronal cell cultures and investigate the cellular and molecular roles of Trappc9 in lipid droplet regulation and vesicle trafficking, and how lack of Trappc9 leads to neuronal dysfunctions. Additionally, the project will investigate how the neuronal abnormalities and the microcephaly phenotype affect the network activity of the cortex and hippocampus in KO mice, which is important for cognitive functions. This aspect of the project will employ electrophysiological approaches. 

You will undertake primary neuron cultures from Trappc9 WT/KO mice and apply lipid droplet analysis techniques, immunocytochemistry and live-cell imaging of neurons with fluorescent markers. Analysis of accumulation and exchange of labelled fatty acids in neuron-glia co-cultures will be part of the project. Other vesicle transport processes, e.g. retrograde transport, might also be investigated. Molecular biology (e.g. GFP-expression constructs, cell transfections) and brain histology methods will be applied in this project, too. Furthermore, in collaboration with the second supervisor at Newcastle University, we intend to investigate how microcephaly might affect cortical and hippocampal neuronal network activity. For this part of the project you will spend 6 months at the second supervisor’s laboratory to undertake electrophysiological experiment.

In addition to these experimental skills, the PhD programme will also provide training in quantitative skills, statistical analysis, data presentation and software applications for biosciences (e.g. image analysis, Python, R, Matlab) through courses at the Universities of Liverpool and Newcastle.

Weblinks:

Lab primary supervisor: https://www.liverpool.ac.uk/translational-medicine/staff/antonius-plagge/

Lab second supervisor: https://www.ncl.ac.uk/medical-sciences/people/profile/fionalebeau.html

Informal enquiries may be made to

HOW TO APPLY

Applications should be made by emailing with a CV and a covering letter, including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project/s and at the selected University. Applications not meeting these criteria will be rejected. We will also require electronic copies of your degree certificates and transcripts.

In addition to the CV and covering letter, please email a completed copy of the Application Details Form (Word document) to , noting the additional details that are required for your application which are listed in this form. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.


Funding Notes

Studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

Liang Z.S., et al; 2020, PLoS Genet. 16(9):e1008916. doi: 10.1371/journal.pgen.1008916
Li C, et al.; EMBO J. 2017, 36:441-457. doi: 10.15252/embj.201694866
Sacher M. et al.; 2019, Traffic 20:5-26. doi: 10.1111/tra.12615
Robson E., et al.; 2018, Neuroscience 377:161-173. doi: 10.1016/j.neuroscience.2018.02.032


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