Neurodevelopmental disorders including autism spectrum disorders are highly prevalent in the Western world, leading to social deficits and intellectual disability. Understanding the underlying mechanisms of human neurodevelopmental disorders caused by gene mutations remains a major challenge. Homozygous mutation of the gene encoding the protein Trafficking Protein Particle Complex Subunit 9 (TRAPPC9) causes Autosomal Recessive Intellectual Disability (AR-ID) characterised by postnatal microcephaly, cerebellar hypoplasia, intellectual disability, obesity, and poor sociability. Using a knockout (KO) model of Trappc9, we are characterising the phenotype of AR-ID using MRI, immunohistochemistry, molecular biology and behaviour assays. We have exciting preliminary data that suggest that microcephaly, behavioural abnormalities and obesity can be replicated in the KO model. However, the metabolic reasons behind AR-ID and obesity remain unknown. Furthermore, it remains to be determined to what extent Trappc9 deficiency affects different brain cell types and how its functions in the brain relate to peripheral tissue symptoms. Using cutting edge quantitative MRI methods to assess brain metabolism and fat composition analysis along with behavioural assays, immunohistochemistry and molecular biology, this project will increase our understanding of the relationship between metabolic abnormalities and AR-ID. Since MRI is used in the clinic, the methods developed have a potential to be translated in assessing patients with such disorders.
The project brings together expertise in cutting-edge preclinical in vivo imaging technology, with neuro-biology and expertise in novel MRS methods to assess neurochemistry and tissue fat. We have developed several methods characterising mouse models of other developmental disorders including autism. This project will expand these to characterise the Trappc9 KO model towards better understanding of the underpinning metabolic causes for AR-ID and obesity in this model. We will utilise fit for purpose behavioural assays and novel imaging methods, for detection and quantification of GABA and glutamate as well as body and visceral fat. Histological and molecular techniques will complement the range of experimental approaches.
Training Available
This cross-departmental and cross institutional collaboration brings complementary expertise in several areas including neuro-imaging, neuro-biology and behavioural biology. The collective backgrounds of the supervisors provide complementary expertise in tackling the complex interplay between genetic mutation, brain structure and metabolism and the project will open new avenues for scientific collaboration on both preclinical and clinical imaging technologies towards better understanding of disease. The student will work in the University of Liverpool Preclinical Imaging facility, to characterise the AR-ID phenotypes in the mouse model using cutting edge imaging assays and behavioural biology. Specifically, the student will gain the following skills: development of in vivo models of AR-ID, quantitative neuro-imaging, histology, molecular biology and metabolism techniques as well as skills in experimental design involving animals. The studentship will also benefit from links to expertise in metabolic methods at the Newcastle University Centre for In Vivo Imaging.
To find out more about the supervisors:
Prof Harish Poptani: https://www.liverpool.ac.uk/systems-molecular-and-integrative-biology/staff/harish-poptani/
Dr Antonius Plagge: https://www.liverpool.ac.uk/systems-molecular-and-integrative-biology/staff/antonius-plagge/
Prof. Andrew Blamire: https://www.ncl.ac.uk/magres/staff/profile/andrewblamire.html#background
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
http://www.dimen.org.uk/how-to-apply/application-overview
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