Investigating the role of Viperin in beta cell survival and the development of type 1 diabetes.

Diabetes currently affects 463 million people worldwide, of which approximately 10% suffer from type 1 diabetes (T1D), the most common form of diabetes in children. During T1D the cells in the pancreas that produce insulin (beta cells) are attacked by the immune system, for reasons we don't yet fully understand, leading to a loss of insulin and increased blood sugar levels and a number of complications. Identifying new ways to prevent the loss of beta cells is vital to develop new treatments for this disease. Likewise, new ways to improve the function and survival of islet transplants (which some T1D patients receive) are urgently needed to improve control of blood sugar.

We have identified that a protein called Viperin, that forms part of the body's immune system, plays a role in controlling beta cell survival following exposure to substances released during immune attack, in vitro (in a dish in the lab). In the present application, we will extend these findings by genetically altering Viperin levels in mouse models of T1D and in mouse islet transplants, to determine if Viperin plays a role in beta cell survival, inflammation and function. We will also explore the mechanisms by which Viperin controls cell survival, and extend our work to human tissue.

Future directions include exploring the role of Viperin in the response of beta cells to systemic viral infection, screening for activators of Viperin (as drug candidates) and investigating Viperin action in other cell types relevant to T1D. If this project validates a protective role for Viperin in beta cells, this will potentially lead to the development of new therapeutic approaches for the treatment of T1D in people, and improvement of clinical islet transplantation.

Aim 1: Determine if genetic loss or gain of Viperin expression alters disease onset or progression in a model of T1D. We will make genetic loss-of-function (Rsad2KO) and gain-of-function (Ins1-Rsad2KI) mice on a diabetes susceptible NOD/ShiLtJ background, to enable objective assessment of the impact of Viperin levels on type 1 diabetes onset/progression and beta cell decline.

Aim2: Investigating the role of Viperin in human beta cell survival and function.
Human islets will be exposed to cytokines ex vivo, with or without knock-down or overexpression of Viperin. An in situ hybridisation approach will be used to screen fixed human T1D pancreatic sections (and non-diabetic controls) for Viperin expression.

Aim 3: Determine if enhancing Viperin expression in beta cells improves islet transplant success in mice. We will transplant our mouse islets overexpressing lenti-Viperin or lenti-GFP into STZ-induced diabetic recipient mice, either as an allogeneic or syngeneic graft. This will enable us to test if sustained Viperin expression can improve islet transplant survival and function.

Aim 4: Investigate the cellular signalling mechanisms by which Viperin regulates cytokine-induced beta cell apoptosis. Finally, we will investigate the roles of UPR signalling/ER stress and oxidative stress, in coupling beta cell inflammation, Viperin expression and apoptosis.