Introduction. There is now little doubt that morbid conditions such as obesity, cardiovascular disease and diabetes are mechanistically linked. Collectively, these conditions represent the biggest risk factors for life threatening diseases including stroke, heart attack and cancer.
Genome wide association studies (GWAS) to determine the causes of obesity and hypertension have identified polymorphisms (SNPs) in potential upstream regulatory regions of a gene called BDNF which is expressed the hypothalamus and other areas of the brain. BDNF has several roles in the brain including mental health, appetite and blood pressure regulation (1, 2,3). Most of these SNPs occur within highly conserved regions around the BDNF gene that may control its expression rather than within the protein coding regions of the gene itself.
Preliminary data. To understand the role of BDNF regulation as a cause of obesity we used bioinformatics. Using molecular biology and primary neuronal culture we show that different alleles of GWAS associated obesity could change the activity of highly conserved enhancer regions that modulate the expression of the BDNF gene in hypothalamic neurones. Recognition of the effects of this SNP on the regulation of BDNF in hypothalamic cells is already an important finding for understanding the causes of obesity. We will used CRISPR genome editing to rapidly and accurately delete this enhancer. The results provide a strong basis for a studentship to further analyse the role of BDNF enhancers and their allelic variants in appetite, weight gain and blood pressure regulation in vivo.
Methods. The successful student candidate will test the effects of removing enhancers on the expression of the BDNF gene in the hypothalamus using in-situ hybridisation (to be supervised by Dr. Perry Barrett, an expert in in-situ hybridisation and feeding studies) and QrtPCR and on the feeding behaviour, blood pressure diabetes risk and metabolism of the mice (supervised by Prof. Mirela Delibegovic an expert in mouse models of obesity and diabetes(4)). CRISPr genome editing will also be used to reproduce the human allelic variants of obesity associated SNPs in these BDNF regulatory regions in mice and these mice will also be tested for resulting changes in gene expression, feeding behaviour, blood pressure and metabolism.
Training offered. This studentship will provide the successful candidate with a unique training experience that combines genome bioinformatics with molecular biology, CRISPR genome editing, RNA expression analysis (QrtPCR and In-situ hybridisation) and in-vivo testing of blood pressure, food intake energy expenditure, glucose and lipid metabolism. Because the majority (>90%) of disease causing genetic variations in the human population are found within the non-coding regulatory genome this combination of bioinformatic, molecular and in-vivo skills will be highly sought after by future employers and funders.
APPLICATION PROCEDURE:
This project is advertised in relation to the research areas of MEDICAL SCIENCES. Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.
NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM.
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