PhD studentship (industry linked 4 years)

Vacancy Reference Number

RW_Angelman_PhD

Closing Date

5 Dec 2024

Salary

Current UKRI Postgraduate student stipend

Address

Royal Holloway University of London, Egham, Surrey, TW20 OEX, UK

Duration

4 years

Further Information

Angelman syndrome is a severe neurodevelopmental disorder, with symptoms including development delay, speech impairment, intellectual disability, epilepsy, and ataxia (1). The syndrome is caused by the deletion or mutation of the ubiquitin E3 ligase A (UBE3A) gene (2). Ketogenic diets represent the gold-standard treatment for Angelman syndrome, however these high fat/low carbohydrate diets can be difficult to maintain (3). Exactly how these diets work in the treatment of Angelman syndrome remains unknown. Our research has focused on understanding how one of these diets, the medium chain triglyceride (MCT) diet, works at a molecular level (4). We have identified specific fats given in this diet that are likely to provide therapeutic outcomes and identified how these fat work at a cellular level (4-6). Through these discoveries, we have developed a new diet with a specific blend of medium chain fatty acids that is clinically effective without difficult carbohydrate restrictions (7). This project will investigate the treatment of Angelman syndrome relating to the newly developed diet. The project will employ a human iPSC cellular model of Angelman Syndrome to investigate this dietary treatment, to characterise effects of these medium chain fatty acids using a range of molecular cell biology approaches. The project will involve distinct research approaches, including various ‘omics’ analyses, cell biology, biochemistry, cell signalling, and pharmacological research. The outcome of this project will be an improved understanding of the treatment of Angelman syndrome by dietary treatments, potentially leading improved patient outcomes.
This will be highly competitive studentship, and applicants with a Masters degree in the area of molecular or cell biology are particularly encouraged to apply.

References
1. M. Cubillos-Rojas et al., The HERC2 ubiquitin ligase is essential for embryonic development and regulates motor coordination. Oncotarget 7, 56083-56106 (2016).
2. A. Owais, R. K. Mishra, H. Kiyokawa, The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders. Cancers (Basel) 12 (2020).
3. J. Duis et al., A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome. Mol Genet Genomic Med 10, e1843 (2022).
4. K. Augustin et al., Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders. Lancet Neurol 17, 84-93 (2018).
5. P. Chang et al., Seizure control by decanoic acid through direct AMPA receptor inhibition. Brain 139, 431-443 (2016).
6. E. C. Warren et al., Decanoic acid inhibits mTORC1 activity independent of glucose and insulin signaling. Proc Natl Acad Sci U S A 117, 23617-23625 (2020).
7. N. E. Schoeler et al., K.Vita: a feasibility study of a blend of medium chain triglycerides to manage drug-resistant epilepsy. Brain Commun 3, fcab160 (2021).

Contact Details

Prof Robin SB Williams, Centre for Biomedical sciences, Department of Biological Sciences, Egham Surrey TW20 OEX. email: robin.williams@rhul.ac.uk