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 在哺乳动物中，由于选择性剪接的差异，存在两种同种型（IR-A和IR-B）。虽然 在文献中提出，IR-A活化是“促有丝分裂的”，IR-B活化是“代谢的”， 由于缺乏工具，关于IR亚型的生物学作用的研究具有挑战性， 研究个体效应。在这里，我们建议开发异构体选择性胰岛素类似物， 结构导向方法和高通量筛选方法的组合。这些异构体 选择性类似物将被开发用于研究探针，以剖析每种IR异构体的作用。这些 工具将使我们能够回答以下问题：1）IR亚型mRNA水平与 蛋白质水平？2)同一个细胞是否会随着时间的推移而具有不同的同种型比例以满足细胞的需求？第三章 IR异构体在体内的分布是否遵循某种逻辑？以及4）每种IR亚型的作用是什么 在每一种细胞类型中，这一领域的研究进展可能会导致新的治疗策略， 人类疾病。

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.