STUDIES ON INSULIN RECEPTOR ISO FORMS

胰岛素和胰岛素受体（IR）参与代谢、增殖和分化。在哺乳动物中， 由于可变剪接的差异，存在两种同种型（IR-A和IR-B）。尽管在《 文献认为IR-A活化是“促有丝分裂”的，IR-B活化是“代谢”的，关于IR-A活化的深入研究表明， 由于缺乏研究个体效应的工具，IR同种型的生物学作用具有挑战性。在这里， 我们建议通过使用结构指导的组合来开发异构体选择性胰岛素类似物， 方法和高通量筛选方法。这些异构体选择性类似物将被开发， 研究探索剖析每个IR同种型的作用。这些工具将使我们能够回答以下问题 问题：1）IR亚型mRNA水平与蛋白水平相关吗？2)是否同一个细胞 异构体比率随时间推移以满足细胞需要？3)IR亚型在体内的分布是否遵循某种类型的 逻辑？和4）在体内每种细胞类型中每种IR同种型的作用是什么？该领域的研究进展可能会 从而为人类疾病带来新的治疗策略。

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.