Rexinoid-Regulated Muscle Gene Expression

描述（申请人提供）：有两类核受体 配体、类维生素A X受体配体（类维生素A）和PPARg配体 （噻唑烷二酮-TZD），其能够在 II型糖尿病的动物模型。在对糖尿病啮齿动物进行的研究中， 我们发现类Rexinoids和TZDs对基因的影响非常不同， 在脂肪组织和骨骼肌中表达。虽然TZD显著 诱导脂肪组织中的基因表达，rexinoids调节 骨骼肌中的基因该项目的目标是描述 Rexinoids胰岛素增敏作用的机制 骨骼肌在肌肉中，类Rexinoids调节基因的表达 与“慢收缩”（I型）肌纤维表型相关（例如， 肌红蛋白和肌钙蛋白I慢）和氧化脂肪酸酶 新陈代谢.由于I型肌纤维（慢收缩纤维）更多的是胰岛素- 比II型（快速收缩）纤维敏感，这是我们的假设， 类Rexinoids通过激活糖尿病动物的 骨骼肌慢收缩基因调控程序。我们将测试这个 通过解决以下三个具体目标： 目的#1研究Rexinoids和钙调神经磷酸酶/ NFAT的相互作用 慢肌收缩基因表达调控的信号转导途径 骨骼肌细胞在体外和体内。 目标2。鉴定介导类Rexinoids作用的核受体 骨骼肌慢收缩基因的表达。 目标3。为了检测类Rexinoids对纤维类型的特异性影响， 糖尿病患者胰岛素敏感性及胰岛素信号转导通路 啮齿动物 Rexinoids是一类全新的胰岛素增敏剂， 通过直接改变骨骼肌中的基因表达来产生影响。 了解它们的作用机制将为新的研究提供新的视角。 糖尿病的治疗和糖尿病并发症的管理的药理学方法 由慢收缩肌纤维丢失引起的肌病的数量 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.