MECHANISM OF ALTERNATIVE SPLICING OF HUMAN INSULIN RECEPTOR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 除了燃料代谢外，胰岛素对生长和发育也是必不可少的。胰岛素受体(IR)有两种不同的变体，不同的是激素结合区域中存在12个氨基酸。INSR基因位于19号染色体上，由22个外显子组成。这两个IR蛋白变异体是由外显子11的选择性剪接而来的。缺失外显子11的IR(IR-A)广泛表达，并与胰岛素和IGF-II结合；含有外显子11的IR(IR-B)分布较有限，主要在胰岛素敏感组织(肝脏、肌肉、脂肪细胞和肾脏)表达，仅与胰岛素结合。胰岛素受体亚型的独特组织分布导致IR-B是代谢受体，IR-A是发育受体，但很少有人对它们不同的生理功能进行定义。 许多低等生物的胰岛素受体基因同源基因控制着生长和寿命，而不是新陈代谢。人们认为，在进化过程中，胰岛素受体的功能被劫持以控制血糖水平。这一次级功能的获得与外显子11的出现相吻合。在含有外显子11的生物体中，如人、猴子和啮齿动物，胰岛素调节葡萄糖的稳态，而在缺乏外显子11的生物体，如果蝇、线虫、河豚(河豚)、埃及伊蚊(蚊子)和池塘蜗牛(池螺)，胰岛素则不调节。然而，在哺乳动物中，胰岛素受体最初控制生长的功能并没有完全被它的代谢作用所抑制，因为胰岛素受体缺失的人类也表现出妖精和胚胎发育迟缓。胰岛素受体的胚胎形式缺乏外显子11，并在新生儿期切换为包括外显子11。这些表达窗口表明，不同的受体亚型具有特定的功能。更重要的是，一些疾病状态，如II型糖尿病、衰老、强直性肌营养不良和癌症，减少了外显子11的包含。这使得IR基因成为研究RNA剪接的一个特别有趣的模型系统。我们在这个项目中的目标是了解这两种异构体的表达是如何在转录后水平上调节的，并确定这两种受体异构体的生理作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Insulin is essential for growth and development in addition to fuel metabolism. There are two variants of the insulin receptor (IR), which differ in the presence of 12-amino acids in the hormone-binding domain. The INSR gene is located on chromosome 19 and composed of 22 exons. The two IR protein variants arise from alternative splicing of exon 11. The IR lacking exon 11 (IR-A) is widely expressed and binds both insulin and IGF-II; the IR containing exon 11 (IR-B) has a more limited distribution, being expressed predominantly in the insulin - sensitive tissues (liver, muscle, adipocytes and kidney) and only binds insulin. The unique tissue distributions of the insulin receptor isoforms has lead to the suggestion that IR-B is the metabolic receptor and IR-A is a developmental receptor, but very little has been done to define their divergent physiological functions. Many lower organisms have insulin receptor gene homologues that control growth and longevity, not metabolism. It is thought that during evolution, insulin receptor function was hijacked to control glucose levels. The acquisition of this secondary function coincides with the appearance of exon 11. In organisms that contain exon 11, such as humans, monkeys, and rodents, insulin regulates glucose homeostasis, but in organisms that lack exon 11, such as Drosophila, C. elegans, Fugu (pufferfish), Aedes aegypti (mosquito) and Lymnaea stagnalis (pond snail), insulin does not. The insulin receptors original function to control growth has not been completely subjugated by its metabolic role in mammals, however, as humans with insulin receptor deletions also exhibit leprechaunism and stunted embryonic growth. The embryonic form of the insulin receptor lacks exon 11 and switches to include exon 11 in the neonatal period. These windows of expression suggest that the different receptor isoforms have specific functions. More importantly, a number of disease states, such as type II diabetes, aging, myotonic dystrophy and cancer, have decreased inclusion of exon 11. This makes the IR gene a particularly interesting model system for studies of RNA splicing. Our goal in this project is to understand how the expression of these two isoforms is regulated at the posttranscriptional level and to determine the physiological roles of the two receptor isoforms.