Title: Altering pancreatic beta cell fate through novel regulators
Funder: The Academy of Medical Sciences

Abstract: Diabetes is a major healthcare problem without a known cure. All forms of diabetes have been associated with pancreatic beta-cell dysfunction. Hence, cell replacement therapies that aim to generate beta-like cells from stem cells have strong potential, reaching clinical trials. A major impediment to the clinical application of this therapy is the blunted glucose sensitivity and insulin secretion of generated cells. A network of transcription factors (TFs) dictate pancreatic beta-cell identity and orchestrate cell-type specific functions such as glucose sensing and insulin secretion. My preliminary analysis suggests that natural and stem-cell generated beta-cells (IPS-B) have significant differences in the expression levels of a number of well-characterized and uncharacterized transcription factors. My hypothesis is that abnormal expression of these TFs in IPS-beta negatively impacts the beta cell transcription factor regulatory network resulting in incomplete cellular phenotypes and function. This proposal aims to identify and characterise previously understudied regulators of pancreatic beta-cell function using a genetic loss-of-function screen to build a more comprehensive understanding of the beta-cell gene regulatory network. Proposed research, which has not been attempted before, will provide the knowledge necessary to correct the gene expression levels of both novel and known beta-cell transcription factors in the IPS-B using novel gene delivery systems. We aim to obtain sustained, long term TF expression levels that will restore the correct gene regulatory networks in the IPS-B, resulting in improved glucose sensitivity and insulin secretion. Our unique approach can remove a major roadblock in the clinical applications of IPS-B.

Lay abstract: Diabetes is a chronic condition that can underlie a number of other serious health conditions making it a major and prevalent healthcare problem worldwide. Unfortunately, due to our modern lifestyle, it is one of the few diseases where the incidence is set to rise dramatically, with projections putting 650 million people at risk by 2040. This condition occurs when the beta-cells, located within the pancreas, dysfunction. While managed with therapy, diabetes has no known cure. Current research aims to generate functional beta-cells in the laboratory environment in order to replace or supplement failing beta-cells of a person living with diabetes. One way to generate beta-cells in the lab is to use induced pluripotent stem (IPS) cells, which have the potential to turn into any cell type of the body. “Beta-like” cells have been generated from IPS cells, which can mimic, but cannot yet replicate all the intricacies of a true beta-cell. In this proposal, we set out to understand the specific roles of a number of novel regulators that orchestrate the making of a beta cell and use this knowledge to generate better functioning beta-cells. Through my collaborative network, we will use a pioneering method to alter the fate of the laboratory generated beta cells to better match their natural equivalents. We believe our unique approach will generate highly functional cells that can be cheaply mass-produced, enabling rapid deployment of this powerful approach in the clinic.

Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE