Roozbeh Akbari Motlagh | ALES Graduate Seminar

Event details: A graduate exam seminar is a presentation of the student’s final research project for their degree.
This is an ALES MSc Final Exam Seminar by Roozbeh Akbari Motlagh. This seminar is open to the general public to attend.

MSc with Dr. Jean Buteau.

Thesis Topic: Small molecule activator of LYN improved the outcome of islet transplantation in mice

Abstract:

Islet transplantation can achieve insulin independence in individuals with type 1 diabetes. However, islets derived from multiple donors are often required, and functional β-cells are lost early after transplantation. Notably, up to 80% of newly transplanted islets are lost due to cell death during the acute post-transplant period. This can be attributed to poor vascularization and the ongoing inflammatory reaction. Thus, strategies are needed to improve graft survival and function, particularly in light of these challenges. Our lab has recently characterized the protein kinase LYN as a novel regulator of β-cell proliferation and survival. We have also shown that, as predicted, a small molecule activator of LYN (called MLR-1023) acted as a “β-cell growth factor” in mice. We herein sought to test the hypothesis that MLR-1023, via its action in β-cells, would improve the outcome of islet transplantation in mice.

To do so, male BALB/c islets were isolated and a marginal mass of 125 islets were transplanted into syngeneic diabetic mice recipients under the left kidney capsule. Recipients were thereafter injected intraperitoneally once daily with MLR-1023 or vehicle for 7 days. An intraperitoneal glucose tolerance test was performed at the end of treatment (days 8) and 21 days after drug withdrawal (day 28). The graft-bearing kidneys and pancreas were harvested for immunohistochemical analysis.

Remarkably, a brief 7-day treatment with MLR-1023 was sufficient to improve glucose tolerance in islet recipients. MLR-1023 significantly increased β-cell proliferation but the effects on β-cell mass were not statistically significant. MLR-1023 significantly accelerated revascularization of the grafts, as observed at day 8. Unfortunately, most of these effects dissipated 21 days after withdrawal but the effect on vascularization was persistent.

These finding holds significant clinical implications. They suggest that MLR-1023 could be used in clinical settings to reduce the required number of islets or to accelerate the time to achieve normoglycemia in islet recipients.