Failure of β-cells to secrete enough insulin contributes to the development of type 2 diabetes, which affects 462 million people worldwide. When poorly treated, diabetes leads to chronic hyperglycaemia that accelerates β-cell failure and the progression of the disease by mechanisms that are not yet clear.
Mitochondria play a central role in β-cell function by integrating glucose metabolism with insulin secretion. Mitochondria fusion and fission processes are essential for quality control and adequate mitochondrial function. Mitochondrial fission process 1 (MTFP1) promotes mitochondrial fragmentation, albeit its biological function in β-cells remains unexplored. We have recently shown that β-cell MTFP1 is directly targeted by miR-125b. This microRNA is regulated by glucose via AMPK (AMP-activated protein kinase) and controls mitochondrial morphology and insulin secretion.
This project aims to elucidate the role of MTFP1 in pancreatic β-cells and to determine whether MTFP1 contributes to the effects of hyperglycaemia, AMPK and miR-125b in β-cell function.
The student will use CRISPR/Cas9 and lentiviral vectors to manipulate MTPF1 in mouse and human islets and β-cell lines and state-of-the-art molecular, cellular and computational biology approaches to perform functional and mechanistic assays. Additionally, the regulation of MTFP1 by glucose and AMPK will be studied in vivo using mice fed diabetes-inducing diets.
The student will be expected to be involved in the design and conduct of experiments, and to publish and present their work at national and international conferences. The student will complete the necessary home office training to receive a personal licence and will be trained in in vitro and in vivo techniques. The PhD student working in this project will be trained in state-of-the-art techniques for the study of beta-cell function as well as in many more conventional molecular and cellular biology techniques that will allow them to acquire a broad skills portfolio which will strongly advance their career. The student will count with the ample expertise of the supervisors’ labs in molecular and β-cell biology as well as in the study of mitochondrial function. It will also count with the support from highly trained staff at Imperial College facilities such as the Imaging, the Flow Cytometry and the BRC Genomics facilities.
The student will acquire further translational skills by regularly attending and presenting at Section meetings, journal clubs and expert seminars and participating in the preparation of manuscripts. They will also have the opportunity to attend and present in national and international conferences.
The ICL Graduate School offers a range of core and specialist transferable skills training courses and the Research Computing Service provides specialized computational training (i.e. programming in R, statistics, machine learning, python). The student will also have the choice to undertake a small amount of teaching in the MSc Applied Genomics, organized by our Section.
The research group of Dr Martinez-Sanchez studies how non-coding RNAs and their gene targets regulate gene expression and β-cell function, with a special interest on the mechanisms leading to β-cell failure in diabetes. Her group is supportive and friendly and works closely with other groups within the Section of Cell Biology and Functional Genomics (Department of Metabolism, Digestion and Reproduction, ICL, currently ranked in the top ten Universities in the world). The Section provides everything necessary for the proposed work (i.e. facilities for islet isolation, cell and tissue culture and routine molecular/cellular biology). We also host confocal/superresolution and widefield microscopes provided by the Facility for Imaging by Light Microscopy and an ultraclean facility for animal maintenance with dedicated support staff. The Section has an excellent publication record in top rated research journals and is well funded from a number of different sources, including grants by the Wellcome Trust, the MRC, the DUK and the EASD. The student will also participate in the activities of the ICL Diabetes Network (https://www.imperial.ac.uk/diabetes-network/) that brings together the many distinguished researchers. The student will be based on the Hammersmith campus: https://www.imperial.ac.uk/visit/campuses/hammersmith/. who are leaders in the field of metabolism and diabetes in the Faculty of Medicine.