University of Liverpool – Institute of Systems, Molecular and Integrative Biology
Supervisors: Dr A Plagge, Dr Kirsty McMillan
Applications accepted all year round
Self-Funded PhD Students Only
About the Project
This project will analyse the cellular functions of the trafficking protein Trappc9 and how deficiency of Trappc9 causes microcephaly and intellectual disability. You will be able to utilise Trappc9 knock-out mice as well as brain organoid cultures as model systems for investigations into brain development, neuronal and neural stem cell biology.
About this opportunity
This PhD project will investigate the cellular functions of the ‘Trafficking protein particle complex subunit 9’ (Trappc9) and its roles in brain development. Mutations of Trappc9 in human and mice cause a neurodevelopmental disorder characterised by postnatal microcephaly, intellectual disability and obesity (Uctepe et al., 2023). Trappc9 is a subunit of the TrappII complex, which is involved in the regulation of vesicle trafficking and cellular lipid droplets (LDs) via interactions with specific Rab proteins (Li et al., 2017; Galindo and Munro, 2023). Within the brain, it is expressed in neurons and neural stem cells. Using Trappc9 knock-out mice, we found a reduced brain size with white and grey matter being affected (Aljuraysi et al., 2024). The hippocampus region showed a disproportionate volume reduction and fewer neural stem cells. Cultured KO neurons display increased LD accumulation and changes in LD-associated proteins. Apart from neurodevelopmental phenotypes, KO mice also become obese with enlarged LDs in adipocytes.
The project aims to characterise changes in KO brain tissue in detail, e.g. by analysing the postnatal development of the hippocampus and the maintenance and differentiation of neural stem cells. Furthermore, it will explore the underlying cellular mechanisms of how Trappc9 deficiency causes these phenotypes, focussing on its roles in LD regulation and lipid metabolism in neurons and neural stem cells. You will be working with brain tissue from KO mice, neuronal cell cultures, fibroblasts and/or adipocytes. The project will also utilise the new technology of brain organoid cultures derived from Trappc9 WT/KO mouse embryonic stem cells. Techniques will involve immunocytochemistry and immunohistochemistry with specific fluorescent markers and advanced microscopy (confocal, live-cell imaging). Various molecular biology techniques will be utilised, e.g. fusion-gene vector construction, cell transfections, qRT-PCR, Western blot, metabolomics etc. Apart from lipid droplet cell biology, vesicle transport processes might also be investigated, for example retrograde transport in neuronal cells. Furthermore, throughout this PhD programme you will be able to access state of the art University research facilities (e.g. Centre for Cell Imaging, Centre for Metabolomics Research). You will also acquire training in quantitative skills, statistical analysis, data presentation and software applications for biosciences (e.g. Imaris image analysis software, Python, R) through courses at the University of Liverpool.
Email your CV, cover letter, project title and reference number to the primary supervisor: Dr Antonius Plagge; plagge@liverpool.ac.uk
In addition to tuition fees, an annual bench fee of £18,000 for laboratory experiments and consumables applies to this project.
References
- Aljuraysi S., et al., (2024) Microcephaly with a disproportionate hippocampal reduction, stem cell loss and neuronal lipid droplet symptoms in Trappc9 KO mice. Neurobiol Dis. 192:106431. https://doi.org/10.1016/j.nbd.2024.106431
- Galindo A. and Munro S., (2023) The TRAPP complexes: oligomeric exchange factors that activate the small GTPases Rab1 and Rab11. FEBS Lett. 597(6):734-749. https://doi.org/10.1002/1873-3468.14553
- Li C., et al., (2017) COPI-TRAPPII activates Rab18 and regulates its lipid droplet association. EMBO J. 36(4):441-457. https://doi.org/10.15252/embj.201694866
- Uctepe E., et al., (2023) TRAPPC9-Related Intellectual Disability: Report of Two New Cases and Review of the Literature. Mol. Syndromol. 14:485-492. https://doi.org/10.1159/000531439
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