Dr. Ron Piran

The Azriely Faculty of Medicine

Pancreatic β-cell regeneration, stabilization and protection in pre-diabetic and diabetic patients

Ron Piran earned his Ph.D. from the Technion in Israel. His decision to devote himself to efforts to find a cure for diabetes evolved out of experiences during his Ph.D. training, which focused primarily on theoretical computer science and formal logic. Using an algebraic modeling method of embryonic development, Dr. Piran predicted and proved the existence of a new biochemical pathway. Dr. Piran took his approach to the Levine lab at SBP, La Jolla CA, where he successfully obtained the prestigious CIRM Fellowship. He studied β-cell regeneration following pancreatic damage. He used his algebraic model to develop new β-cells from α-cell conversion – an important new pathway for β-cell neogenesis. Dr. Piran made major progress in understanding the molecular mechanism by which that process occurred, and isolated a druggable cell receptor, which holds promise for clinical application.

 

Abstract

All type I and some type II diabetes patients are suffering from the loss of the insulin expressing b-cells. Therefore, b-cell regeneration has garnered great interest as an approach to personalized diabetes therapy. We developed a model of pancreatic damage, combining pancreatic duct ligation with b-cell ablation, which led to the induction of a novel pathway for b-cell neogenesis in which a-cells from preexisting islets transdifferentiated into neogenic b-cells. Using a candidate approach, we identified the PAR2 receptor as having properties that could play a role in the transdifferentiation process. To test that idea, mice had their β-cells ablated and were injected with PAR2 agonist. A similar experiment preformed in PAR2 knockout (PAR2KO) mice has shown no regeneration of b-cells. The finding of efficient a- to b-cell conversion raises the prospect that b-cell regeneration may be feasible. Caerulein injected to PAR2KO mice led to specific b-cell death. Selective b-cell loss is a cardinal feature of T1, and also occurs in T2. This supported the hypothesis that PAR2 is a key mediator of b-cell death in diabetes. The mechanism by which b-cells are destroyed without affecting a- or δ-cells, which are related in terms of location, development, and gene expression, is not understood. To our knowledge, this is the first example of a single gene capable to mediate selective b-cell death in response to an external trigger. Using a commercial C-peptide assay, we will recognize the diabetic and pre-diabetic patient individuals that suffers from β-cell loss. Then, we will stabilize β-cells in these patients and by using PAR2 modulation to regenerate them in β-deficient patients that already developed diabetes.

 

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