The role of non-canonical IKKs in metabolic disease

描述(申请人提供)：非典型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性代谢性疾病的重要代谢介质。在高通量筛选IKK抑制剂？我们确认了FDA批准的药物氨来昔诺，它是一种IKK？/TBK1特异性抑制剂。与我们的假设一致，给肥胖小鼠服用氨来昔芬可以产生可逆的体重减轻、胰岛素敏感性和肝脏脂肪变性的缓解，而不影响食物摄入量。由于IKK-epsilon和TBK1在肝脏和脂肪中的活性随着肥胖的反应而升高，而且众所周知，这些组织的代谢活动可以相互影响，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。使用氨来昔诺作为一种工具，在肥胖背景下当IKK-epsilon/TBK1活性较高时，强烈抑制它们，我希望找出IKK-epsilon和TBK1下游的主要信号通路。我们之前已经发表了IKK-epsilon在代谢性疾病中的作用。在这里，我建议使用氨来昔诺治疗IKK-epsilon基因敲除小鼠，以及肝脏特异性的TBK1基因敲除和过度表达，具体研究另一种非典型性IKK在代谢性疾病的发生和持续发展中的作用。最后，还将利用肝脏特异的IKK-epsilon过表达来研究IKK-epsilon在肝脏中的特异性作用。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，并有望导致治疗或预防这些破坏性疾病的新的治疗方法。 与公共健康相关：世界范围内的肥胖率正在迅速上升，对公共健康构成重大威胁。在这里，我们建议调查非典型性IKK在肥胖相关代谢性疾病发展中的作用。这项研究将有助于对代谢性疾病的基本了解，并有望导致治疗或预防这些破坏性疾病的新的治疗方法。

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. PUBLIC HEALTH RELEVANCE: World-wide obesity rates are increasing rapidly, posing a significant threat to public health. Here we propose to investigate the role of non-canonical IKKs in the development of obesity-associated metabolic diseases. 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.