The role of non-canonical IKKs in metabolic disease

非典型 IKK 在代谢疾病中的作用

基本信息

批准号：
8719095
负责人：
Shannon Marie Reilly
金额：
$ 5.51万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8719095
关键词：
Adenoviruses Adipose tissue Affect Antibodies Antisense Oligonucleotides Body Weight decreased Cardiovascular Diseases Cells Chronic Complex Cultured Cells Data Development Diabetes Mellitus Diet Disease Eating Enzyme Inhibition Evaluation Event FDA approved Fatty Liver Fatty acid glycerol esters Genes Genetic Health Hepatic Hyperlipidemia IKKepsilon Immune Immunoblotting Immunoprecipitation Infiltration Inflammation Inflammatory Insulin Resistance Knock-out Knockout Mice Laboratories Lead Liver Liver diseases Mediator of activation protein Metabolic Metabolic Diseases Metabolism Molecular Mus Nature Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Overnutrition Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Proteins Proteomics Public Health Publishing Regulation Research Resistance Role Signal Pathway Syndrome TANK-binding kinase 1 Testing Time Tissues amlexanox attenuation cytokine feeding high throughput screening improved inhibitor/antagonist insulin sensitivity interest liver metabolism mouse model mutant non-alcoholic fatty liver novel therapeutic intervention overexpression prevent programs research study response small hairpin RNA tool

项目摘要

DESCRIPTION (provided by applicant): The role of non-canonical IKKs in metabolic disease We hypothesize that hepatic IKK-epsilon and TBK1 are important metabolic mediators affecting hepatic steatosis and systemic metabolic disease. In a high throughput screen for inhibitors of IKK? kinase activity, we identified the FDA approved drug, amlexanox, which we confirmed to be an IKK?/TBK1 specific inhibitor. Consistent with our hypothesis, administration of amlexanox to obese mice produces reversible weight loss, insulin sensitivity and attenuation of hepatic steatosis, without affecting food intake. Since the activities of IKK-epsilon and TBK1 are elevated in both liver and fat in response to obesity, and since it is well known that the metaboli activities of these tissues can impact each other, the tissue and cell autonomous nature of these effects remains uncertain. I will attempt to evaluate whether the impact of IKK-epsilon/TBK1 blockade on hepatic metabolism is direct or indirect. Using amlexanox as a tool to acutely inhibit IKK-epsilon/TBK1 in the context of obesity when their activity is high, I hope to identify the primary signaling pathways downstream of IKK-epsilon and TBK1. We have previously published on the role of IKK-epsilon in metabolic disease. Here I propose to specifically investigate the role of TBK1, the other non-canonical IKK, in the development and persistence of metabolic disease, using Amlexanox treatment in IKK-epsilon knockout mice, as well as liver specific TBK1 knockdown and overexpression. Finally the liver specific role of IKK- epsilon will also be investigated using hepatic-specific IKK-epsilon overexpression. The results of these experiments will illuminate the role of hepatic IKK-epsilon and TBK1 in liver metabolism as well as systemic metabolic regulation. This research will contribute to the basic understanding of metabolic diseases and hopefully lead to new therapeutic approaches to treat or prevent these devastating disorders.

描述（由申请人提供）：非典型 IKK 在代谢疾病中的作用我们假设肝脏 IKK-epsilon 和 TBK1 是影响肝脂肪变性和全身代谢疾病的重要代谢介质。高通量筛选 IKK 抑制剂？根据激酶活性，我们鉴定出了 FDA 批准的药物 amlexanox，我们确认它是 IKK?/TBK1 特异性抑制剂。与我们的假设一致，对肥胖小鼠施用氨来呫诺可产生可逆的体重减轻、胰岛素敏感性和肝脏脂肪变性的减弱，而不影响食物摄入。由于肝脏和脂肪中 IKK-epsilon 和 TBK1 的活性因肥胖而升高，并且众所周知，这些组织的代谢活动可以相互影响，因此这些影响的组织和细胞自主性质仍然不确定。我将尝试评估 IKK-epsilon/TBK1 阻断对肝脏代谢的影响是直接还是间接。在肥胖背景下，当 IKK-epsilon/TBK1 活性较高时，使用 amlexanox 作为工具来急性抑制 IKK-epsilon/TBK1，我希望确定 IKK-epsilon 和 TBK1 下游的主要信号通路。我们之前发表过有关 IKK-epsilon 在代谢疾病中的作用的文章。在这里，我建议使用 Amlexanox 治疗 IKK-epsilon 敲除小鼠，以及肝脏特异性 TBK1 敲低和过度表达，专门研究 TBK1（另一种非典型 IKK）在代谢疾病的发生和持续中的作用。最后，还将使用肝脏特异性 IKK-ε 过表达来研究 IKK-ε 的肝脏特异性作用。这些实验的结果将阐明肝脏 IKK-epsilon 和 TBK1 在肝脏代谢以及全身代谢调节中的作用。这项研究将有助于对代谢疾病的基本了解，并有望带来治疗或预防这些破坏性疾病的新治疗方法。