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：
8280394
负责人：
JOHN C YOON
金额：
$ 8.93万
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8280394
关键词：
Adaptor Signaling Protein Affect Aging Alleles Animal Model Biogenesis Biological Cell Culture Techniques Cell Proliferation Cells ChIP-on-chip 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.

描述（由申请人提供）：对线粒体功能障碍和胰岛素抵抗之间的潜在连接引起了极大的兴趣。在我们的研究中，为了鉴定线粒体生物发生和功能的新型调节剂，我们发现培养的肌肉细胞中的Wnt激活会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胰岛素受体底物-1（IRS-1）。尽管Wnt信号网络主要是在细胞增殖，分化和发育过程的背景下进行的，但现在有新兴的证据涉及代谢中的Wnt信号传导。特别是，已经记录了Wnt途径基因的等位基因变化与对2型糖尿病的敏感性之间的密切关联。现在，我们试图评估Wnt信号传导的功能损失可以在肌肉细胞中产生胰岛素抵抗的可能性。在AIM 1中，我们将使用Wnt拮抗剂评估使用细胞培养和动物模型抑制Wnt信号对肌肉中线粒体生理和胰岛素敏感性的影响。在AIM 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检查非典型和规范WNT信号通路之间的功能相互作用。细胞培养和动物模型都将被利用。我们还计划通过基因表达分析和芯片芯片实验来鉴定这两种途径的下游靶标。这些研究将使我们更清楚地定义Wnt信号在细胞和全身代谢中的作用，并可能导致结果直接与人类2型糖尿病的发病机理有关。对关键组织中WNT信号的定向操纵可能可能转化为2型糖尿病的治疗干预措施。