ILPR: A Novel Drug Target for Activation of the Human Insulin Gene

Supervisors: Dr John Barrow, Prof Kevin Docherty and Prof Matteo Zanda

The insulin-linked polymorphic region (ILPR) is a region of DNA that lies next to the insulin gene and is able to control levels of insulin expression. ILPR DNA sequences adopt a highly ordered structure called a G-quadruplex, which has been shown to alter insulin gene activity depending on the length of the ILPR sequence. Controlling the activity of the ILPR would allow for control of the insulin gene, which in turn will provide a possible route to therapy for diabetes.

Diabetes is caused by a complete lack of insulin due to the absence of beta-cells in the pancreas, or by inactive insulin, so diabetic patients must inject insulin daily in order to survive. If we can control the production of insulin through this novel ILPR target then it will provide a route to the production of functional insulin in other cells of the body or possibly as an extra therapy alongside current diabetes drug treatments.

This project has three main aims:

1. Adapt current ILPR binding drug candidate molecules to enhance their ILPR specificity.
2. Functionally characterise these drug candidates in mammalian cell lines and isolated human islets.
3. Understand the physical mechanisms that control ILPR G-quadruplex function.