CONTROL OF ADIPOGENESIS AND METABOLISM BY INSULIN

描述（改编自申请人的摘要）：本项目的长期目标 研究的目的是确定参与调节的分子机制， 胰岛素和胰岛素样生长促进脂肪细胞分化和代谢 因素 参与这些过程的信号转导途径是 不完全理解，虽然几个组成部分， 胰岛素刺激的途径已经被鉴定和表征。 的 这个提议的中心假设是， 在胰岛素受体的胞质结构域激活时， 受体酪氨酸激酶，并且这些信号单独和/或共同起作用。 组合以引起对细胞命运和代谢的多效性作用 这是胰岛素作用的特征。 嵌合受体cDNA 由细胞外组成。 殖民地配体结合区 刺激因子-I（CSF-1）受体剪接至跨膜， 已经构建了胰岛素受体的胞质结构域， 这个假设。 CSF/IR的表达使得CSF-1能够模拟表达IL-10的能力。 胰岛素和IGF I启动成脂肪细胞分化， 葡萄糖转运而不激活内源性胰岛素受体。 此外，CSF IR/IR的胞质结构域内的突变 抑制胰岛素的离散作用，同时使其他作用保持完整。 这 模型系统将被用来检查所使用的分子机制， 胰岛素和IGF I调节脂肪细胞分化和代谢 其中包括： 胰岛素受体亚结构域和磷酸化位点的作用 胞质结构域在将受体信号耦合到诱导中， 脂肪形成的重要介质的活性。 的贡献 Ras蛋白介导IGF-1/胰岛素刺激诱导的 胰岛素Ras/Raf/MEK/MAP激酶调节剂的能力 影响胰岛素受体胞质结构域能力的途径 以诱导脂肪形成。 亚结构域和磷酸化位点的作用 在胰岛素受体胞质结构域中调节脂肪细胞 包括激活葡萄糖转运和抑制 脂肪分解

DESCRIPTION (Adapted from applicant's abstract): The long term goal of this research is to define molecular mechanisms involved in the regulation of adipocyte differentiation and metabolism by insulin and insulin-like growth factors. The signal transduction pathways involved in these processes are not fully understood, though integral components of several insulin-stimulated pathways have been identified and characterized. The central hypothesis of this proposal is that multiple, distinct signals emanate from the insulin receptor cytoplasmic domain upon activation of the receptor tyrosine kinase, and that those signals act separately and/or in combination to elicit the pleiotropic effects on cell fate and metabolism that are characteristic of insulin action. A chimeric receptor cDNA consisting of the extracellular. ligand-binding domain of the colony stimulating factor-l (CSF-l ) receptor spliced to the transmembrane and cytoplasmic domains of the insulin receptor has been constructed to test this hypothesis. Expression of the CSF/IR allows CSF-l to mimic the ability of insulin and IGF I to initiate adipoblast differentiation and to activate glucose transport without activation of endogenous insulin receptors. Furthermore, mutations within the cytoplasmic domain of the CSF IR/IR inhibit discrete actions of insulin while leavened others intact. This model system will be used to examine the molecular mechanisms used by insulin and IGF I to regulate adipocyte differentiation and metabolism including the following: The role of subdomains and phosphorylation sites within the insulin receptor cytoplasmic domain in coupling receptor signals to the induction and activity of important mediators of adipogenesis. The contribution of the Ras proteins in mediating the IGF l/insulin-stimulated induction of adipogenesis The capacity of modulators of Ins Ras/Raf/MEK/MAP kinase pathway to influence the ability of the insulin receptor cytoplasmic domain to induce adipogenesis. The role of subdomains and phosphorylation sites within the insulin receptor cytoplasmic domain in regulation of adipocyte metabolism including activation of glucose transport and inhibition of lipolysis.