Mitochondrial regulators and insulin signaling

描述（由申请人提供）：线粒体功能障碍和胰岛素抵抗之间的潜在联系一直备受关注。在我们鉴定线粒体生物发生和功能的新型调节剂的研究中，我们发现培养的肌肉细胞中的Wnt活化诱导线粒体增殖并增强胰岛素敏感性，部分通过诱导衔接蛋白胰岛素受体底物-1（IRS-1）。虽然Wnt信号传导网络主要在细胞增殖、分化和发育过程的背景下进行了研究，但现在新出现的证据表明Wnt信号传导参与了代谢。特别是，Wnt途径基因的等位基因变异与2型糖尿病易感性之间的强相关性已被证明。我们现在试图评估Wnt信号传导功能丧失可在肌肉细胞中产生胰岛素抵抗的可能性。在目标1中，我们将使用Wnt拮抗剂来评估抑制Wnt信号传导对肌肉中线粒体生理学和胰岛素敏感性的影响，使用细胞培养和动物模型。在目标2中，我们将研究非经典和经典Wnt信号通路在肌肉线粒体生理学和胰岛素敏感性方面的功能相互作用。将使用细胞培养和动物模型。我们还计划通过基因表达谱分析和ChIP芯片实验来确定这两个途径的下游靶点。这些研究将使我们能够更清楚地定义Wnt信号在细胞和全身代谢中的作用，并可能导致与人类2型糖尿病发病机制直接相关的结果。在关键组织中直接操纵Wnt信号可能会转化为2型糖尿病的治疗干预。

DESCRIPTION (provided by applicant): There has been much interest in the potential connection between mitochondrial dysfunction and insulin resistance. In our studies to identify novel regulators of mitochondrial biogenesis and function, we have found that Wnt activation in cultured muscle cells induces mitochondrial proliferation and enhances insulin sensitivity, in part through the induction of the adaptor protein insulin receptor substrate-1 (IRS-1). While the Wnt signaling network has been studied primarily in the contexts of cell proliferation, differentiation, and developmental processes, an emerging body of evidence now implicates Wnt signaling in metabolism. In particular, a strong association between allelic variations in Wnt pathway genes and the susceptibility to type 2 diabetes has been documented. We now seek to evaluate the possibility that a functional loss of Wnt signaling can produce insulin resistance in muscle cells. In Aim 1, we will use Wnt antagonists to assess the effect of inhibiting Wnt signaling on mitochondrial physiology and insulin sensitivity in muscle, using both cell culture and animal models. In Aim 2, we will examine the functional interactions between the non-canonical and the canonical Wnt signaling pathways in the context of mitochondrial physiology and insulin sensitivity in muscle. Both cell culture and animal models will be utilized. We also plan to identify the downstream targets of these two pathways by gene expression profiling and ChIP-on-chip experiments. These studies will allow us to more clearly define the role of Wnt signaling in cellular and systemic metabolism, and may lead to results with a direct bearing on the pathogenesis of human type 2 diabetes. A directed manipulation of Wnt signaling in key tissues may potentially translate into therapeutic interventions for type 2 diabetes.