Objective
Our objective is to find new therapeutic targets to increase beta cell regeneration through replication of existing beta cells. We will do so by systematically knocking down all genes in the genome to find those that can increase beta cell proliferation.
Background Rationale
Regenerating beta cells in a type 1 diabetes patient has many potential advantages over laboratory grown beta-like cells. Own own beta cells are placed directly downstream of the gut -- a perfect place for them to sense incoming nutrients. They are also positioned directly upstream of the liver, so insulin secreted can quickly act on a highly important target organ. Finally, our own beta cells are connected to the brain with specialized nerves that allow them to begin to secrete insulin even before the food is absorbed by the gut. This allows anticipation of meals and better glucose control. Current strategies for replacement lack some or all of these advantages. While chemical inhibitors of a protein called DYRK1A have been shown to increase human beta cell replication, we believe that more targets exist.
Description of Project
Type 1 diabetes is caused by autoimmune attack on the pancreatic beta cell. The cure for type 1 diabetes must involve replacing or regenerating these critical cells (likely combined with some type of immunosuppression). While great inroads have been made, there are still very few ways to induce human beta cell replication. In the first part of this grant, we propose to study a novel receptor expressed on the human beta cell that may inhibit human beta cell replication, survival and insulin secretion. If our hypothesis is correct, these studies would provide the impetus to develop antagonists to this receptor as potential therapeutics for type 1 diabetes patients. In the second part of this grant, we propose to test all genes in the genome for their ability to induce human beta cell replication. Taken together, our identification of new genes and pathways that control human beta cell replication will lead to novel treatments to regenerate beta cells in type 1 diabetes patients.
Anticipated Outcome
We anticipate that completion of this grant will provide the evidence to develop drugs targeting GPCR-X as novel therapeutics to improve human beta cell proliferation and regeneration. We also anticipate finding novel genes that can regulate human beta cell proliferation.
Relevance to T1D
This proposal will test every known gene in the genome to identify all genes that could increase human beta cell proliferation. We will prioritize studying genes that have the potential to lead to new therapeutics to improve beta cell mass in type 1 diabetes patients.