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Investigation of the role of insulin receptor in chromosome stability.

研究胰岛素受体在染色体稳定性中的作用。

基本信息

批准号：
10795222
负责人：
Eunhee Choi
金额：
$ 6.18万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-05 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10795222
关键词：
10 year old Administrative Supplement Cell Differentiation process Cell Proliferation Cell division Cell membrane Cell surface Cells Cellular Metabolic Process Chromosomal Stability Chromosome Segregation Clinical Treatment Crowding Diabetes Mellitus Disease Ensure Fluorescence Funding Future Goals Grant Growth Growth Factor Health Homeostasis Human Hyperinsulinism Immune Insulin Insulin Receptor Investigation Knowledge MAP Kinase Gene Malignant Neoplasms Metabolic Mitogens Mitosis Non-Insulin-Dependent Diabetes Mellitus Nutrient Organism PIK3CG gene Pathway interactions Physiological Proliferating Proto-Oncogene Proteins c-akt Reader Reagent Receptor Mediated Signal Transduction Receptor Signaling Regulation Research Risk Role Schedule Signal Pathway Signal Transduction Therapeutic Time Tissues Translational Research cancer cell cancer immunotherapy extracellular novel receptor function spatiotemporal tumor growth

项目摘要

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.

项目摘要多细胞生物发展受体介导的信号转导，由细胞外生长因子启动，增殖。胰岛素是一种生长因子，高胰岛素血症可促进和维持肿瘤的发生增长胰岛素受体（IR）定位于细胞表面质膜，无论是在代谢组织细胞中还是在代谢组织细胞中。高度增殖的细胞，如免疫细胞和癌细胞。IR激活两个下游信号通路， PI 3 K-AKT途径和MAPK途径，以调节细胞代谢、增殖和生长。尽管 IR信号在系统稳态中的有趣发现，营养信号如何维持染色体稳定性仍然不确定。我们知识上的这一差距是我们理解胰岛素在细胞增殖和分化中的作用及其对人体健康的影响，如高胰岛素血症，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如何确保有丝分裂中染色体的准确分离，以及IR的生理作用是什么？ IR在细胞分裂中的功能;（2）IR如何选择性激活PI 3 K-AKT相对于MAPK信号传导分支;和 (3)在细胞增殖和分化中IR功能还需要哪些其他因素？为了实现我们的目标，我们正在申请微孔板阅读器的管理补充资料（BMG Labtech的ESTIOstar Plus）。所有项目我们的资助金都依赖于这个酶标仪。到目前为止，我们一直在借用类似的时间酶标仪的指纹由于机器上拥挤，很难安排时间插槽，并对机器的使用有限制。目前共享的酶标仪超过十岁，其荧光灵敏度低，需要大量的试剂和限制应用.总的来说，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。此外，我们的研究将可能作为进一步转化研究和未来治疗高胰岛素血症和2型糖尿病的基础。糖尿病与某些癌症的风险增加有关，也可能导致癌症免疫疗法