The role of non-canonical IKKs in metabolic disease

描述（由申请人提供）：非经典IKK在代谢性疾病中的作用我们假设肝脏IKK-TK和TBK 1是影响肝脏脂肪变性和全身性代谢性疾病的重要代谢介质。在高通量筛选抑制剂IKK？激酶活性，我们确定了FDA批准的药物，氨来诺，我们证实是一个IKK？/ TBK 1特异性抑制剂。与我们的假设一致，氨来占诺给药肥胖小鼠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。由于IKK-ERK和TBK 1的活性在肝脏和脂肪中响应于肥胖而升高，并且由于众所周知这些组织的代谢活性可以相互影响，因此这些效应的组织和细胞自主性质仍然不确定。我将尝试评估IKK-BK 1/TBK 1阻断对肝脏代谢的影响是直接的还是间接的。在肥胖的背景下，当IKK-β 1/TBK 1的活性高时，使用氨来赞作为急性抑制IKK-β 1/TBK 1的工具，我希望能够确定IKK-β 1和TBK 1下游的主要信号通路。我们之前已经发表了IKK-kD在代谢性疾病中的作用。在这里，我建议专门研究TBK 1的作用，其他非典型的IKK，在代谢疾病的发展和持久性，使用氨来赞治疗IKK-IKK基因敲除小鼠，以及肝脏特异性TBK 1敲低和过表达。最后，还将使用肝脏特异性IKK-Kl的过表达来研究IKK-Kl的肝脏特异性作用。这些实验的结果将阐明肝脏IKK-ERK和TBK 1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破坏性疾病。

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.