Autoimmune destruction of insulin-producing β-cells of the pancreas results in Type 1 Diabetes (T1D), with an incidence rate of 25.4 out of 100,000 (0-14 years) in the UK. Despite improvement of care, to-date, there is no cure for T1D, presenting an urgent need for new clinical strategies.
Current knowledge of what connects the adaptive immune system to the beta-cells is limited. Pancreatic islets are complex micro-organs, where in addition to hormone releasing cells (Fig 1), antigen presenting cells of the myeloid lineage are also present. We recently identified the neuropeptide Y (NPY) receptors, NPYR 1, 4 and 5, as novel targets for promoting human beta-cell survival. Using selective ligands, we revealed NPY Y1, 4 and 5 engage a powerful anti-apoptotic pathway, protecting mouse and human islets from damage, helping to preserve beta-cell mass and functionality. This demonstrates proof of concept for targeting these receptors to treat Type 1 diabetes.
Our flow cytometry analysis of murine islet cells identified the Y5 receptor to be present on a CD45+ cell population (Fig 2), suggesting action at this receptor in this population of resident islet immune cells is beneficial for the health of the beta-cell. This project proposes to examine the role of Y5 receptor in protecting pancreatic islets from auto-immune mediated damage and thereby identify a lead target strategy to enable the translation of a new therapy for T1D.
1. Explore the role of Y5 activation on murine and human native islets.
2. To determine whether Y5 is the missing link between distressed ß-cells and the adaptive immune system.
3. Determine the clinical utility of Y5 agonist on preserving beta-cell mass functionality in T1D.