IGF-II AND MUSCLE CELL DIFFERENTIATION

描述(改编自申请人的摘要)：通过 体液和/或自分泌/旁分泌机制，胰岛素样生长 刺激肌肉细胞分化的因素。而IGF-I和IGF-I IGF-II刺激肌肉生成，IGF-II是主要的IGF多肽 由肌肉细胞表达，因此很可能发挥更多的 在分化过程中的基础作用。本提案中的研究 将检验IGF-II刺激肌肉细胞分化的假设 通过增加肌生成素的表达和作用，分化 骨骼肌的主控基因。此外，研究将测试 假设IGF-II对肌生成素表达的影响是中介的 通过IGF-I受体和IGF结合蛋白调节 胰岛素样生长因子对肌肉生成素表达和骨骼肌分化的影响。 为了检验这些假设，研究将涉及以下具体目标： (1)检测胰岛素样生长因子-II(IGF-II)对大鼠肺组织中IGF-II基因表达的影响。 蛋白质的生物合成，以及肌肉生成素与DNA调控元件的结合， 转录因子E12和ID的表达 肌生成素与其发生二聚化的主要多肽；(2)检测IGF- 受体亚型介导IGF-II对血管内皮生长因子表达的影响 肌肉生成素、E12和ID，使用最近定义的IGF-II类似物，具有 IGF-II受体的选择性亲和力在结合、交联和 MRNA丰度研究；以及(3)探讨IGF-1的潜在作用。 结合蛋白和IGF诱导的IGF诱导的肌生成素基因表达 类似物，对结合蛋白的亲和力降低，但亲和力不变 胰岛素样生长因子受体。

DESCRIPTION (Adapted from the applicant's abstract): Acting through humoral and/or autocrine/paracrine mechanisms, the insulin-like growth factors stimulate the differentiation of muscle cells. Whereas both IGF-I and IGF-II stimulate myogenesis, IGF-II is the principle IGF peptide expressed by muscle cells and is, therefore, likely to play a more fundamental role in the differentiation process.Studies in this proposal will test the hypothesis that IGF-II stimulates muscle cell differentiation by increasing the expression and action of myogenin, a differentiation master control gene for skeletal muscle.In addition, studies will test the hypothesis that the effects of IGF-II on myogenin expression are mediated through the IGF-I receptor and that IGF-binding proteins modulate the effects of IGF on myogenin expression and skeletal muscle differentiation. To test these hypotheses, studies will address the following specific aims: (1) To examine the effects of IGF-II on the mRNA abundance, transcription, protein biosynthesis, and binding of myogenin onto DNA regulatory elements, and on the expression of the transcription factors, E12 and Id, the principal peptides with which myogenin dimerizes; (2) to examine which IGF- receptor subtypes mediate the effects of IGF-II on the expression of myogenin and E12 and Id, using recently defined IGF-II analogs that have selective affinity for the IGF-II receptor in binding, cross-linking, and mRNA abundance studies; and (3) to explore the potential role of IGF- binding proteins and IGF-induced myogenin gene expression with an IGF analog with reduced affinity for binding proteins but unaltered affinity for IGF receptors.