The role of non-canonical IKKs in metabolic disease

描述（申请人提供）：非规范IKKs在代谢性疾病中的作用我们假设肝脏IKK-epsilon和TBK1是影响肝脏脂肪变性和全身代谢性疾病的重要代谢介质。在高通量筛选IKK？激酶活性，我们发现了FDA批准的药物，氨lexanox，我们确认它是IKK？/TBK1特异性抑制剂。与我们的假设一致，肥胖小鼠服用氨lexanox可以产生可逆的体重减轻，胰岛素敏感性和肝脂肪变性的衰减，而不影响食物摄入量。由于肥胖导致肝脏和脂肪中IKK-epsilon和TBK1的活性升高，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的还是间接的。在肥胖背景下，当IKK-epsilon/TBK1活性高时，利用amlexanox作为工具，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。我们之前发表过关于IKK-epsilon在代谢性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敲除和过表达，专门研究TBK1（另一种非规范IKK）在代谢性疾病的发生和持续中的作用。最后，我们还将通过肝脏特异性IKK-epsilon过表达来研究IKK-epsilon的肝脏特异性作用。这些实验结果将阐明肝脏IKK-epsilon和TBK1在肝脏代谢和全身代谢调节中的作用。这项研究将有助于对代谢性疾病的基本了解，并有望导致新的治疗方法来治疗或预防这些毁灭性的疾病。

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.