Investigation of the role of insulin receptor in chromosome stability.

项目总结 多细胞生物发展由细胞外生长因子启动的受体介导的信号转导 扩散。长期以来，胰岛素一直被认为是一种生长因子，高胰岛素血症可以促进和维持肿瘤 成长。胰岛素受体(IR)定位于细胞表面质膜，在代谢组织细胞和 高度增殖的细胞，如免疫细胞和癌细胞。IR激活两条下游信号通路， PI3K-AKT通路和MAPK通路，调节细胞代谢、增殖和生长。尽管 IR信号在系统内稳态中的有趣发现，营养信号如何维持染色体 稳定性仍不确定。我们知识上的这一鸿沟是我们理解 胰岛素在细胞增殖和分化中的作用及其对人类健康的影响 与包括2型糖尿病和癌症在内的各种疾病有关。我们的目标是探索以下内容 问题：(1)IR如何在有丝分裂中确保准确的染色体分离，以及生理上的 IR在细胞分裂中的作用；(2)IR如何选择性地激活PI3K-AKT与MAPK信号分支； (3)IR在细胞增殖和分化中的作用还需要哪些其他因素？为了达到我们的目标，我们 要求为微板阅读器(CLARIOstar Plus，BMG LabTech)提供管理补充。所有项目 我们资助的资金的多少都依赖于这个微型读卡器。到目前为止，我们一直在借用类似的时间 属于我们同事的微板阅读器。由于机器上很拥挤，很难安排时间 插槽，并且对机器的使用有限制。目前的共享微板阅读器 十年，对荧光的敏感性低，需要大量的试剂和限制 申请。总而言之，拟议的研究将促进我们对功能、调节和 胰岛素在生理细胞增殖和分化中的作用机制(S)。此外，我们的研究将 可能为进一步的翻译研究和未来的治疗方法，如高胰岛素血症和2型 糖尿病与某些癌症的风险增加有关，也可能被用于治疗癌症。 免疫疗法。

PROJECT SUMMARY Multicellular organisms develop receptor-mediated signal transduction initiated by extracellular growth factors to proliferate. Insulin has long been known as a growth factor, and hyperinsulinemia can promote and sustain tumor growth. Insulin receptor (IR) localizes to the cell surface plasma membrane both in metabolic tissue cells and in highly proliferative cells such as immune cells and cancer cells. IR activates two downstream signaling pathways, the PI3K-AKT pathway and the MAPK pathway, to regulate cell metabolism, proliferation, and growth. Despite intriguing findings for IR signaling in systemic homeostasis, how the nutrient signaling maintains chromosome stability still remains uncertain. This gap in our knowledge presents a key barrier to our understanding of the function of insulin in cell proliferation and differentiation and its impact on human health, as hyperinsulinemia is associated with various diseases including type 2 diabetes and cancer. Our goals are to explore the following questions: (1) how does IR ensure accurate chromosome segregation in mitosis, and what is the physiological function for IR in cell division; (2) how does IR selectively activate the PI3K-AKT vs. MAPK signaling branch; and (3) what other factors are required for IR function in cell proliferation and differentiation? To reach our goals, we are requesting an administrative supplement for microplate reader (CLARIOstar Plus, BMG Labtech). All projects of our funded grant depend on this microplate reader. Until now, we have been borrowing time on a similar microplate reader belonging to our colleague. Due to crowding on the machines, it is difficult to schedule time slots, and there are restrictions on the use of the machine. The current shared microplate reader is more than ten years old, and its sensitivity to fluorescence is low, requiring large amounts of reagents and limiting applications. Collectively, the proposed research will advance our understanding of the function, regulation, and mechanism(s) of insulin action in physiological cell proliferation and differentiation. Furthermore, our studies will likely serve as a basis for further translational research and future therapeutics as hyperinsulinemia and type 2 diabetes are associated with increased risks for certain cancers and may also be harnessed for cancer immunotherapies.