Rexinoid-Regulated Muscle Gene Expression

描述（由申请人提供）：核受体有两类 配体、类视黄醇 X 受体配体 (rexinoids) 和 PPARg 配体 （噻唑烷二酮类-TZD）能够诱导胰岛素敏化 II型糖尿病的动物模型。在糖尿病啮齿动物中进行的研究中， 我们发现rexinoids和TZDs对基因有非常不同的影响 在脂肪组织和骨骼肌中表达。虽然 TZD 明显 诱导脂肪组织中的基因表达，rexinoids 调节 骨骼肌中的基因。该项目的目标是表征 Rexinoids 的胰岛素增敏作用的机制 骨骼肌。在肌肉中，rexinoids 调节基因的表达 与“慢肌纤维”（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（慢肌纤维）含有更多的胰岛素 - 比 II 型（快肌）纤维更敏感，我们的假设是 Rexinoids 通过激活糖尿病动物诱导胰岛素敏感性 骨骼肌中的慢肌基因调节程序。我们将测试这个 通过解决以下三个具体目标的假设： 目标 #1 研究 rexinoids 和钙调神经磷酸酶 / NFAT 的相互作用 信号转导通路在慢肌基因表达调控中的作用 骨骼肌细胞在体外和体内。 目标#2。鉴定介导类毒素作用的核受体 骨骼肌中慢肌基因表达的影响。 目标#3。检查纤维类型 - rexinoids 对纤维的特定影响 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，可产生其 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 因慢肌纤维丧失而引起的肌病数量 表达。

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.