Rexinoid-Regulated Muscle Gene Expression

描述(申请人提供)：有两类核受体 配体、维甲酸X受体配体(Rexinoid)和PPARg配体 (噻唑烷二酮-TZDS)，能够诱导胰岛素敏化 II型糖尿病的动物模型。在糖尿病啮齿动物身上进行的研究中， 我们发现Rexinoid和TZDS对基因的影响是非常不同的 在脂肪组织和骨骼肌中均有表达。而TZDS则明显 诱导脂肪组织基因表达，雷公藤红素调节基因表达 骨骼肌中的基因。这个项目的目标是描述 雷公藤多苷对大鼠胰岛素增敏作用的机制 骨骼肌。在肌肉中，rexinoid调节基因的表达 与“慢抽动”(类型I)肌纤维表型(如 肌红蛋白和肌钙蛋白I慢)和氧化脂肪酸的酶 新陈代谢。由于I型肌纤维(慢抽动纤维)更多地是胰岛素- 比II型(快速抽搐)纤维更敏感，我们的假设是 雷公藤红素通过激活胰岛素受体诱导糖尿病动物的胰岛素敏化 骨骼肌中的慢抽动基因调控程序。我们将对此进行测试 通过解决以下三个具体目标提出假设： 目的1研究雷公藤红素与钙调神经磷酸酶/NFAT的相互作用 慢抽动基因表达调控中的信号转导途径 骨骼肌细胞在体外和体内。 目的#2.确定介导雷公藤红素效应的核受体 骨骼肌中慢抽动基因表达的研究。 目的#3.研究Rexinoid对纤维类型的特定影响 糖尿病患者的胰岛素敏感性与胰岛素信号转导途径 啮齿动物。 雷克西诺是一类全新的胰岛素增敏剂，它能产生 通过直接改变骨骼肌中的基因表达来发挥作用。 了解它们的作用机制将为小说提供新的见解 治疗糖尿病和管理糖尿病的药理学方法 由于慢抽动肌纤维丢失而引起的肌病的数量 表情。

DESCRIPTION (provided by applicant): There are two classes of nuclear receptor ligands, Retinoid X Receptor ligands (rexinoids) and PPARg ligands (thiazolidinediones-TZDs) that are capable of inducing insulin sensitization in animal models of Type II Diabetes. In studies carried out in diabetic rodents, we have found that rexinoids and TZDs have very different effects on gene expression in both adipose tissue and skeletal muscle. While TZDs markedly induce gene expression in adipose tissue, rexinoids regulate the expression of genes in skeletal muscle. The goal of this project is to characterize the mechanisms involved in the insulin - sensitizing effect of rexinoids in skeletal muscle. In muscle, rexinoids regulate the expression of genes associated with the "slow twitch" (Type I) myofiber phenotype (such as myoglobin and Troponin I slow) and the enzymes of oxidative fatty acid metabolism. Since Type I myofibers (slow twitch fibers) are more insulin - sensitive than Type II (fast twitch) fibers, it is our hypothesis that rexinoids induce insulin sensitization in diabetic animals by activating the slow twitch gene regulatory program in skeletal muscle. We will test this hypothesis by addressing the following three specific aims: Aim #1 To investigate the interactions of rexinoids and calcineurin / NFAT signal transduction pathway in the regulation of slow twitch gene expression in skeletal muscle cells in vitro and in vivo. Aim #2. To identify the nuclear receptors that mediate the effects of rexinoids on slow twitch gene expression in skeletal muscle. Aim #3. To examine the fiber type - specific effects of rexinoids on the insulin sensitivity and the insulin signal transduction pathway in diabetic rodents. Rexinoids are an entirely novel class of insulin sensitizers that produce their effects by directly altering gene expression in the skeletal muscle. Understanding their mechanisms of action will provide new insights into novel pharmacologic approaches to the treatment of diabetes and the management of a number of myopathies that arise from the loss of the slow twitch myofiber expression.