Type I Diabetes

Rationale
Auto-immune destruction of insulin-producing beta cells in the pancreas underlies type I diabetes (T1D). Protection of beta cells, including those that can be derived from stem cells and transplanted to the patient, can prevent or reverse disease progression. Our collaborators at the Joslin Diabetes Center have discovered that knockout of renalase in beta cells protects against stress-induced cell death. Under-characterization and controversies in the literature on the enzymatic function of renalase have resulted in a poor understanding of the role of this enzyme in human biology and more specifically in beta cell destruction. Targeting renalase with inhibitors could lead to the development of drugs to treat type I diabetes.

What we're doing
Structural analysis of renalase revealed that this enzyme is analogous to monoamine oxidases with a similar FAD-binding domain and a rather large binding site that can be targeted with small molecules. We have discovered that certain monoamine oxidase inhibitors also inhibit renalase, particularly pargyline. Together with our collaborators we have shown that pargyline administration partially recapitulates complete loss of renalase in various assays, including in mouse models of T1D. We are very excited to leverage our expertise in protein structural and functional analysis as well as rational drug design strategies to thoroughly characterize renalase and develop highly potent and specific inhibitors.

x

Publication Highlights

Cai EP, Ishikawa Y, Zhang W, Leite NC, Li J, Hou S, Kiaf B, Hollister-Lock J, Kurt Yilmaz N, Schiffer CA, Melton DA, Kissler S, Yi P. “Genome-scale in vivo CRISPR screen identifies RNLS as a target for beta cell protection in type 1 diabetes” at Nature Metabolism, Vol. 2, Iss. 9, pp. 934-945 (2020).