Desmoglein-2: A novel lifeline to treat diabetes

Pancreatic islet transplantation is the only cure for type 1 diabetes (T1D), but outcomes are limited by the rapid death of the insulin producing beta islet cells
and the poor revascularisation of the graft once transplanted.
The cross-talk between beta islet cells and endothelial cells (ECs, the cells which form the inner lining of blood vessels) is known to be mutually beneficial
but the mechanisms underpinning this process are still unclear. We have identified the cell surface adhesion molecule desmogelin-2 (DSG2) to be expressed
by both beta islet cells and ECs. This project will investigate whether DSG2 mediates a cross-talk between beta islet cells and ECs via a DSG2:DSG2
homotypic interaction and whether intracellular signalling events stemming from this interaction promotes cell survival, proliferation and function.
Herein, we will use knock-down and over-expression approaches to alter DSG2 levels in a pancreatic beta islet cell and a pancreatic EC line. We will
interrogate these lines (and others) for cell-cell interactions, signalling, proliferation, survival and functional readouts (eg insulin production and
vascularisation). We will also test the importance of DSG2 in diabetes by comparing mouse models of T1D in wildtype versus our DSG2-knock-out strain of
mice. Mouse models of islet transplantation will be used to confirm these findings. Next, we will confirm a role for DSG2 in diabetes by comparing DSG2
expression levels (mRNA and protein) on beta islet cells from healthy and diabetic patients. Finally, having established the importance of DSG2 in diabetes,
we will develop a range of DSG2-bound biomaterials (eg nanospheres and polymer scaffolds) and test their ability to support beta islet and EC
survival/function. This nanotechnology will then be tested for improved cure rates in diabetic mice following transplantation.