Research Description
Despite notable improvement in treatments with exogenous insulin, they often cannot achieve a tight glucose control and, consequently, over time, many Type 1 Diabetes (T1D) patients develop secondary complications, such as retinopathy and neuropathy. Thus, the ultimate goal to accomplish a definitive cure for T1D is to replace the lost beta-cell mass. This could be done by transplantation of pancreatic islets or stem cell-derived insulin-producing cells, by in situ regeneration or by trans-differentiation. However, any replacement will irrevocably succumb to the same autoimmune attack that killed the original beta-cells. Thus, it is of the utmost importance to develop strategies to preserve newly generated or transplanted pancreatic islets. Unfortunately, many approaches aiming at restoring tolerance by manipulating immune cells have been tested and, although safe, have shown only limited efficacy. Inflammatory processes, infections or major life style changes can easily alter the balance again towards immune activation. We recently discovered the existence of immune privileged stem cells in the skin and muscle and found their protection was not dependent on a physical barrier in an immune privileged site. Instead, it is a cell-autonomous process that allows independent cloaking from activated T cells. Here we propose to exploit the molecular circuits controlling this striking phenomenon (that already naturally occurs in our bodies) to provide similar protection to susceptible beta-cells. Since this will be a cell-intrinsic mechanism of immune evasion, changes in overall immune function should not alter their privileged status allowing for long-lasting survival of newly regenerated or transplanted beta-cellsResearch Profile
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?A true cure for type 1 diabetes involves replacement of missing insulin producing beta-cells. However, unfortunately, current approaches for transplantation of beta-cells are limited due to attack by the patients' immune cells and, hence, these patients require long-term strong immune-suppression, which puts them at serious risk of infection and even cancer. The goal of this project is to develop strategies to ensure the survival of transplanted or regenerated beta-cells, by allowing them to effectively and safely cloak from immune cells. Moreover, these approaches will also benefit type 2 diabetic patients that require exogenous insulin and patients with genetic variants of insulin dependent diabetes, since it will enable transplant of stem cell derived beta-cells, even when there is not a perfect match from the source and the recipient patient.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?The long-term objective of our work in to make islet/beta-cell transplant a feasible and safe reality, by ensuring that these precious cells, once in the patient, are not killed by immune cells. By restoring insulin-producing beta-cells in patients, we expect to free them from constant glucose monitoring and insulin injections. Moreover, a better regulation of blood glucose levels will reduce the side-effects associated to poor glucose control, such as retinopathy or neuropathy.
Why important for you, personally, to become involved in diabetes research? What role will this award play?I initiated my work in beta-cell regeneration and diabetes in 2002, when I started my masters and then I continued this work during my PhD. After 6 years working on strategies to re-grow beta-cells, I transitioned to train in immunology, so I could understand how an immune attack works (and therefore, how it could be stopped). This award is allowing me to bring all this experience and a life-time work together to develop novel strategies to safely replace missing beta-cells in patients without the need of immune-suppression. Insulin injections have saved the lives of millions of diabetic patients, but they are far from being perfect. Daily manage of glucose levels is very challenging, and hypoglycemic shocks are dangerous, and scary to both patients and their loved ones. This award will help us to investigate strategies to restore insulin-producing cells and hopefully one day achieve proper glucose and insulin control in all diabetics.
In what direction do you see the future of diabetes research going?I think research in type 1 diabetes will be focused on two related areas: a) better approaches for transplantation and survival of newly replaced beta-cells, and b) better treatments to stop the immune attack against beta-cells, mostly in people at risk. In type 2 diabetes, I think a better understanding of the role of the immune system will also be key. It has been known for a long time the important role of inflammation in insulin resistance and beta-cell dysfunction (improper insulin secretion). Developing means to reduce this deleterious effect of immune cells and immune molecules in type 2 diabetes will open many new avenues.