Insulin and insulin receptor (IR) are involved in metabolism, proliferation and differentiation. In mammals, two isoforms (IR-A and IR-B) exist due to differences in alternative splicing. Although it was suggested in the literature that IR-A activation is ?mitogenic? and IR-B activation is ?metabolic?, in-depth investigations about the biological roles of the IR isoforms are challenging due to the lack of tools to study the individual effects. Here, we propose to develop isoform-selective insulin analogues by using a combination of structure-guided approach and a high-throughput screening approach. These iso-form selective analogues will be developed to research probes to dissect the roles of each IR isoform. These tools will enable us to answer the following questions: 1) Do IR isoform mRNA levels correlate with protein levels? 2) Could the same cell have different isoform ratio overtime to address cellular need? 3) Does IR isoform distribution in vivo follow some type of logic? and 4) What is the role of each IR isoform in each cell type in vivo? Research progress in this field may lead to new therapeutic strategies for human diseases.
We are developing novel insulin molecules specific to insulin receptor isoforms to learn the roles of each insulin receptor in vivo. Successful outcome will lead to new strategies for treating human diseases.
|Disotuar, Maria M; Petersen, Mark E; Nogueira, Jason M et al. (2018) Synthesis of hydrophobic insulin-based peptides using a helping hand strategy. Org Biomol Chem :|