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Mitochondrial regulators and insulin signaling

线粒体调节剂和胰岛素信号传导

基本信息

批准号：
8177576
负责人：
JOHN C YOON
金额：
$ 8.92万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8177576
关键词：
Adaptor Signaling Protein Affect Aging Alleles Animal Model Biogenesis Biological Cell Culture Techniques Cell Proliferation Cells Complementary DNA DNA copy number Data Developmental Process Diagnostic Disease Dominant-Negative Mutation Dose Electroporation Event Gene Expression Gene Expression Profiling Generations Genes Genetic Screening Glycogen Human Insulin Insulin Resistance Intramuscular Injections Lead Link Measures Mediating Membrane Potentials Metabolic Metabolic syndrome Metabolism Mitochondria Mitochondrial DNA Mus Muscle Muscle Cells Myoblasts Non-Insulin-Dependent Diabetes Mellitus Oxygen Consumption Pathogenesis Pathway interactions Phenotype Physiological Physiology Predisposition Production Protein Binding Proteins RNA Interference Reactive Oxygen Species Regulation Role Signal Pathway Signal Transduction Skeletal Muscle Stem Cell Development Susceptibility Gene TCF7L2 gene Therapeutic Therapeutic Intervention Tissues Translating Variant WNT5A gene Wnt proteins base density functional genomics functional loss gain of function human disease in vivo inhibitor/antagonist insight insulin receptor substrate 1 protein insulin sensitivity insulin signaling interest lipid biosynthesis loss of function mitochondrial dysfunction mitochondrial membrane novel overexpression promoter protein expression research study response self-renewal tumorigenesis

项目摘要

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. PUBLIC HEALTH RELEVANCE: We are studying genes involved in the regulation of mitochondria and exploring their connections to insulin sensitivity. This may lead to information useful for diagnostic or therapeutic applications for type 2 diabetes.

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很有兴趣。在我们寻找线粒体生物发生和功能的新调节因子的研究中，我们发现在培养的肌肉细胞中Wnt激活诱导线粒体增殖和增强胰岛素敏感性，部分是通过诱导适配蛋白胰岛素受体底物-1(IRS-1)来实现的。虽然Wnt信号网络主要在细胞增殖、分化和发育过程中进行研究，但现在有大量证据表明Wnt信号与新陈代谢有关。特别是，Wnt途径基因的等位基因变异与2型糖尿病的易感性之间存在很强的相关性。我们现在试图评估Wnt信号的功能缺失可能会在肌肉细胞中产生胰岛素抵抗。在目标1中，我们将使用Wnt拮抗剂，通过细胞培养和动物模型来评估抑制Wnt信号对肌肉线粒体生理学和胰岛素敏感性的影响。在目标2中，我们将在线粒体生理学和肌肉中胰岛素敏感性的背景下，研究非典范和典范的Wnt信号通路之间的功能相互作用。将同时使用细胞培养和动物模型。我们还计划通过基因表达谱和芯片实验来确定这两条通路的下游靶点。这些研究将使我们能够更清楚地确定Wnt信号在细胞和系统代谢中的作用，并可能导致与人类2型糖尿病发病机制直接相关的结果。对关键组织中Wnt信号的定向操作可能会转化为对2型糖尿病的治疗干预。与公共健康相关：我们正在研究参与线粒体调控的基因，并探索它们与胰岛素敏感性的关系。这可能会为2型糖尿病的诊断或治疗应用提供有用的信息。