INTRACELLULAR RECEPTORS AND METABOLIC CONTROL

细胞内受体和代谢控制

• 批准号: 3876998
• 负责人: D S MILLER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3876998
• 关键词: Xenopus; antibody; biological signal transduction; cell nucleus; cytoplasm; egg /ovum; genetic transcription; genetic translation; growth factor; insulin; insulin receptor; metabolism; microinjections; peptide hormone; receptor; single cell analysis

Complex organisms use chemical signals to integrate and coordinate the function of specialized tissues. In many cases, information is transferred in the form of chemicals, e.g., polypeptide hormones or growth factors, which interact with target cells through specific, surface receptors and profoundly affect cell structure and function. This project is concerned with the question of how such information flows to intracellular metabolic control points, i.e., defining postreceptor signalling mechanisms. Recent-research has focussed on the role of intracellular receptors in the overall mechanism of insulin action. For these studies, we have developed a powerful experimental system consisting of a giant, insulin-sensitive cell (amphibian oocyte), paraffin oil-based cell microinjection and fractionation procedures and single cell microanalysis. Using this system, we have obtained the first evidence that intracellular insulin can directly affect cell metabolism. That is, microinjected, intracellular insulin stimulates both transcription and translation by acting at nuclear and cytoplasmic sites. Such actions are independent of the surface receptor, since they also occur in isolated nuclei and cytoplasm samples. Insulin action at internal sites also occurs when cells are exposed to extracellular hormone, since the insulin-stimulated component of protein synthesis is partially blocked when cells are first exposed to external hormone and then microinjected with antibody. Inhibition by antibody is only found in cells which have accumulated undegraded insulin intracellularly. Future plans include 1) defining the mechanisms by which insulin gains access to the internal receptors and through them affects metabolism, 2) determining the extent to which intracellular receptors are involved in the action polypeptide hormones and growth factors in somatic cells, and 3) assessing the role of disrupted intracellular signalling in pathological states, e.g., insulin resistance.

复杂的生物体利用化学信号整合和协调 特殊组织的功能。在许多情况下，信息被转移到 以化学品的形式，例如，多肽激素或生长因子， 其通过特异性表面受体与靶细胞相互作用， 深刻影响细胞结构和功能。这个项目关注的是 这些信息如何流向细胞内代谢的问题， 控制点，即，定义后受体信号机制。 最近的研究集中在细胞内受体在细胞凋亡中的作用。 胰岛素作用的总体机制。对于这些研究，我们开发了一个 一个强大的实验系统， （两栖类卵母细胞），石蜡油基细胞显微注射和 分级分离程序和单细胞微量分析。使用这个系统， 我们已经获得了细胞内胰岛素可以直接 影响细胞新陈代谢。也就是说，显微注射，细胞内胰岛素 通过作用于细胞核， 细胞质位点。这种作用不依赖于表面受体， 因为它们也出现在分离的细胞核和细胞质样品中。胰岛素 当细胞暴露于 细胞外激素，因为蛋白质的胰岛素刺激成分 当细胞第一次暴露于外部环境时， 激素，然后显微注射抗体。抗体的抑制作用是 只在积累了未降解胰岛素的细胞中发现 细胞内。 未来的计划包括：1）确定胰岛素增加的机制 进入内部受体并通过它们影响新陈代谢，2） 确定细胞内受体参与的程度， 体细胞中的作用多肽激素和生长因子，和3） 评估破坏的细胞内信号传导在病理学中的作用 国家，例如，胰岛素抵抗