Congenital hyperinsulinism models for novel drug discovery
Awardee: Michael Kalwat
Institution: Indiana Biosciences Research Institute
Grant Amount: $70,200.00
Funding Period: February 1, 2024 - January 31, 2025
Summary:
Patients with congenital hyperinsulinism (HI) are in a continual battle to regulate their blood glucose levels. HI is caused by genetic mutations that lead to inappropriately high insulin levels in the blood. Insulin is normally released from beta cells within the pancreas only after meals when blood glucose is elevated. However, in HI these cells are dysfunctional and release too much insulin even when glucose levels are low. The only FDA-approved drug for HI, diazoxide, has side-effects and some patients are unresponsive. Therefore, new treatments need to be developed. To accomplish this requires the creation of new methods that allow us to test drugs on cells which mimic the human disease. In our project, we will create a human beta cell model that mimics HI and we will test new drugs to determine their ability to suppress insulin release and their mechanisms of action. Our project is broken into two Aims. In Aim 1, we will create a human β-cell line that expresses a mutant version of a gene found in HI. We will use this line alongside normal β-cells to test our new drug compounds. In Aim 2, we will collaborate with a medicinal chemist to improve the effectiveness of our top candidate compound and we will perform experiments to identify exactly which proteins are involved in our drug’s actions. We anticipate that the success of this project will propel our lab’s progress in HI research and enable us to develop improved model systems and make discoveries that will benefit HI patients.