STUDIES ON INSULIN RECEPTOR ISO FORMS

胰岛素受体异构体的研究

• 批准号: 10251229
• 负责人: Danny Hung-Chieh Chou
• 金额: $ 38.8万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251229
• 关键词: Address; Alternative Splicing; Biological; Cells; Individual; Insulin; Insulin Receptor; Investigation; Lead; Learning; Literature; Logic; Mammals; Messenger RNA; Metabolic; Metabolism; Outcome; Protein Isoforms; Proteins; Research; Role; Structure; analog; cell type; high throughput screening; human disease; in vivo; novel; novel therapeutic intervention; tool

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.

胰岛素及其受体(IR)参与新陈代谢、增殖和分化。在哺乳动物身上， 由于选择性剪接的不同，存在两种异构体(IR-A和IR-B)。尽管它是在 文献表明IR-A的激活是“有丝分裂的”，而IR-B的激活是“代谢的”。 由于缺乏研究个体效应的工具，IR亚型的生物学作用具有挑战性。这里, 我们建议利用结构导向的组合来开发具有异构体选择性的胰岛素类似物 方法和高通量筛选方法。这些同构型选择性类似物将被开发成 研究探索剖析每一种IR亚型的作用。这些工具将使我们能够回答以下问题 问题：1)IR异构体mRNA水平与蛋白质水平相关吗？2)同一细胞可能有不同的 异构体比率超时以满足细胞需求？3)体内IR异构体分布是否遵循某种类型 逻辑？4)每种IR异构体在体内每种细胞类型中的作用是什么？这一领域的研究进展可能 为人类疾病带来新的治疗策略。