Role of miRNAs in pancreatic beta-cell function

Diabetes affects 8% of the world population and its incidence continues to rise unabated. Central to the development of diabetes is the failure of beta-cells, which are dispersed throughout the pancreas in the islets of Langerhans. Failing beta cells are unable to secrete enough insulin to lower blood sugar levels and a deeper understanding of the molecules that control beta-cell function and survival is essential for the development of better targeted drugs that can prevent, slow down or even reverse beta cell demise and hence effectively treat diabetes.

MicroRNAs (miRNAs) are small non-coding RNAs that silence gene expression post-transcriptionally. There are more than 2000 different miRNAs in the human body that can virtually modulate every biological process and disease. Our work (Martinez-Sanchez et al., Mol Endoc, 2015) and that of others has demonstrated that miRNAs are essential for β-cell development and function and have recently been proposed as enforcers of beta-cell identity (differentiation). It has also been demonstrated that alteration of miRNAs can lead to diabetes. Nevertheless, very little is known about which miRNAs are important for beta-cell function, how they exert their influence and how their actions are controlled.

Our most recent work (Kone et al., FASEB J, 2014) demonstrate that the expression of several miRNAs is controlled by the cellular energy sensor AMPK (AMP-activated protein kinase). AMPK is involved in the control of glucose homeostasis and a suggested target of commonly-used anti-diabetic drugs, although its mechanism of action in the insulin-secreting beta-cell remains unclear. Our studies in vitro demonstrate that the overexpression of one of these miRNAs alters beta-cell differentiation and function. This project aims to decipher the mechanism by which AMPK regulates the expression of this miRNA and to assess its function in mouse and human beta-cells in vivo. To do so, the candidate will apply a series of in vitro and in vivo techniques such as cell culture and manipulation, generation and characterization of transgenic models and, in collaboration with Dr Salem, a novel technique to transplant islets into the anterior chamber of the eye which can then be imaged using confocal microscopy.

Provided training and skills:
The successful applicant will be joining an internationally-renowned research group, within one of the world’s top research universities. The Division has an excellent publication record in top rated research journals and is well funded from several different sources.
Full training will be given in miRNA (and RNA) biology, beta-cell/islet biology, regulation of gene expression and the generation and use of models for the study of miRNA function and diabetes in vivo. More specifically, the student will develop:
- Research-specific skills (in vitro): Biochemistry and Molecular biology (Protein preparation and analysis, cloning, RNA and DNA isolation, RT-qPCR, etc), Cell Biology (cell culture, transfection, virus production, immunostaining, etc), Islet Biology (Isolation, imaging, secretion, etc), miRNA Biology (purification, manipulation, quantification, target study, etc)
- Research-specific skills (in vivo): Transgenic generation, breeding, genotyping, handling, isolation of cells and organs, etc
- Bioinformatics: MiRNAs target prediction and analysis, database searching, Microsoft office package, Basic programming skills (Bash, R, for High through put sequencing)

Additionally, the student will develop other general research highly transferable skills such as critical thinking, ethics, time and project management, oral and written communication skills, leadership and networking, teamwork and problem solving
The student will also be expected to present his/her data in regular seminars and in appropriate international conferences. Teaching opportunities within a MSc course will also be provided.

Enquiries and full applications including an up-to-date curriculum vitae and the names and addresses of two academic referees should be sent to Dr Aida Martinez-Sanchez ([Email Address Removed]). More information and references can be found at Imperial Website: http://www.imperial.ac.uk/people/a.martinez-sanchez