Objective
To discover new genes made by white blood cells in the islet that may play a role in beta cell regeneration, and therefore may be new factors that could be used to restore beta cells in T1D.
Background Rationale
The discovery of new approaches to restore insulin-producing beta cells in T1D has potential as a therapeutic approach. There are few molecules known to regenerate new beta cells in humans. We and others have found that a certain type of white blood cell that resides in the pancreatic islet may be a rich source of such compounds. Under certain stresses such as following the death of beta cells, macrophages can be induced to turn on production of genes and proteins that might stimulate the generation of new beta cells or enhance the function of existing beta cells. Here we hope to exploit this unique characteristic of macrophages to try to discover new genes and proteins that may stimulate human beta cell regeneration and have potential as T1D therapy.
Description of Project
Macrophages are a type of white blood cell that are known as the "garbage eaters" of the body, eating dead cells and bacteria to remove them safely. They likely play a role in T1D by helping to activate the immune system. It is also emerging that macrophages serve a number of other important roles in the body, including tissue repair and wound healing, by producing certain proteins (growth factors and cytokines) that can stimulate replication and repair of cells and tissue. In the pancreas, every islet – the clusters of insulin-producing beta cells that are subject to immune attack in T1D – has 5-10 macrophages. Our work and that of others has shown that macrophages in the islet can respond to certain stresses such as death of insulin-producing beta cells by producing potent growthfactors and other substances that may stimulate the production of new beta cells or improve their function. It is remarkable that only a few macrophages in each islet could have such profound effects on islet beta cells, by producing potent substances that affect neighbouring beta cells. Here we propose to discover new genes and proteins made by islet macrophages in humans that are potential stimulators of beta cell regeneration. We will stress human islets in the lab to induce the expression of regenerative genes in islet macrophages, isolate the macrophages, and identify the genes by an approach known as RNA sequencing. We will then test the most promising candidates for their ability to stimulate new beta cell formation and enhance the function of existing beta cells. Through this work we hope to discover new pathways for stimulating restoration of beta cells in T1D.
Anticipated Outcome
We anticipate that at the end of this 2-year study, we will have identified a list of genes that are induced in macrophages in the islet that may be stimulators of human beta cell regeneration. We will have further tested a few of the lead candidate proteins that are produced by these genes for their ability to induce new human beta cell formation and enhance human beta cell function. We thus anticipate identifying several new candidate proteins as beta cell therapies in T1D.
Relevance to T1D
In T1D, beta cells are killed and lose function in the face to autoimmune attack. Finding new ways to restore functioning beta cells in T1D is an essential step towards a cure. The discovery of new genes and pathways involved in human beta cell regeneration and function could lead to the development of new drugs that target the beta cell for restoration in T1D.