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Precision Medicine DTP – Using Omics to Understand the Genes and Pathways Underlying Alcohol Use Disorder


College of Medicine and Veterinary Medicine

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Dr K Evans , Dr T-K Clarke , Dr S Glerup No more applications being accepted Competition Funded PhD Project (European/UK Students Only)

About the Project

Background

Alcohol misuse is a huge public health problem, and those who attempt to curtail consumption can be hampered by highly aversive withdrawal symptoms. We have shown that knockout of the Sorcs2 gene in mice leads to a decrease in alcohol preference (as well as decreased symptoms of withdrawal)1. Furthermore, exposure to alcohol and alcohol withdrawal both increase SORCS2 expression in a human neuron-like cell line2. In keeping with this, SNPs in the SORCS2 gene are associated with serious alcohol withdrawal symptoms in humans2. The associated haplotype disrupts transcription factor binding motifs within a stress hormone-responsive enhancer that is active in neural tissue. Thus, SORCS2 is linked to alcohol use and alcohol withdrawal. The mechanism(s) underlying these observations are not currently understood. We have generated human dopaminergic neuronal lines that lack the SORCS2 gene (manuscript in preparation). The dopaminergic system, which we have shown is altered in Sorcs2 knockout mice3, plays a key role in alcohol-induced responses in the brain. If we can characterise the cellular response to alcohol (and alcohol withdrawal) in the presence and absence of SORCS2 then this should shed light on the pathways implicated in alcohol misuse and withdrawal difficulties and may suggest targets for future treatment development. In a second strand to the project, the student will follow up some recent findings from our lab. We have implicated SORCS2 in DNA damage: mice and human dopaminergic neuronal cells lacking SORCS2 both exhibit a greater number of DNA double stranded breaks (DSBs) than wild-type cells (manuscript in preparation). Alcohol is also known to cause formation of DNA DSBs. As both alcohol misuse and DNA DSBs are linked to neurodegeneration, determining whether alcohol treatment exacerbates the DNA DSB phenotype of the SORCS2 knockout lines is of interest in understanding SORCS2’s cellular role with respect to alcohol.

Aims

We aim to use omics techniques, such as DNA methylation analysis, RNA seq and proteomics, to generate profiles in human neuronal cells allowing comparison of wild-type cells to those either lacking or over-expressing SORCS2 with and without alcohol exposure. In addition to using the datasets generated to infer the genes, proteins and pathways implicated, we will compare them to those datasets currently (and shortly) available to us via the Generation Scotland cohort (https://www.ed.ac.uk/generation-scotland). For example, we have blood-based DNA methylation profiles available for 8161 individuals and our recent epigenome-wide association study of this data has identified 2504 differentially methylated CpG sites associated with alcohol use (manuscript in preparation). The student will also use immunocytochemistry techniques to determine whether alcohol treatment exacerbates the DNA DSB phenotype of the SORCS2 knockout lines. If this is found to be the case then the genomic impact will be investigated, for example, the position of the breaks will be mapped using chromatin immunoprecipitation followed by sequence analysis (ChIP-seq). These analyses together with the analysis of the cell line and blood-derived omic datasets, singly and in combination, should lead to a greater understanding of the processes and pathways impacted by alcohol.

Training outcomes

The student will gain skills in laboratory and statistical data analysis techniques. Laboratory skills include a variety of cell and molecular biology techniques. They will become adept at handling and managing large genomic datasets and will learn to evaluate the strengths and weaknesses of their data. They will acquire skills in programming (using R and Python), statistical and bioinformatics analyses. They will develop their communication skills and their ability to evaluate both the literature and their own data critically.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.

For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2020

Qualifications criteria: Applicants applying for a MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualification, in an appropriate science/technology area.
Residence criteria: The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £15,009 (RCUK rate 2019/20) for UK and EU nationals that meet all required eligibility criteria.

Full eligibility details are available: http://www.mrc.ac.uk/skills-careers/studentships/studentship-guidance/student-eligibility-requirements/

Enquiries regarding programme: [Email Address Removed]

References

1. Olsen, D., Kaas, M., Lundhede, J., Molgaard, S., Nykjær, A., Kjolby, M., Østergaard, S.D., and Glerup, S. (2019). Reduced alcohol seeking and withdrawal symptoms in mice lacking the BDNF receptor sorcs2. Front. Pharmacol. 10, 499.
2. Smith, A.H., Ovesen, P.L., Skeldal, S., Yeo, S., Jensen, K.P., Olsen, D., Diazgranados, N., Zhao, H., Farrer, L.A., Goldman, D., et al. (2018). Risk locus identification ties alcohol withdrawal symptoms to SORCS2. Alcohol. Clin. Exp. Res. 42, 2337–2348.
3. Glerup, S., Olsen, D., Vaegter, C.B., Gustafsen, C., Sjoegaard, S.S., Hermey, G., Kjolby, M., Molgaard, S., Ulrichsen, M., Boggild, S., et al. (2014). SorCS2 regulates dopaminergic wiring and is processed into an apoptotic two-chain receptor in peripheral glia. Neuron 82, 1074–1087.



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