Probing the relevance of the "counter-inflammatory" noncanonical IkB kinases in r

描述（由申请人提供）：本提案侧重于评价新假设的临床概念验证研究。我们假设非经典Ikb激酶IKKe和TBK 1是“抗炎”激酶，它们在抑制炎症通路的同时帮助支持正能量平衡。因此，选择性地抑制该途径将改善正能量平衡和由炎症支持的胰岛素抵抗。为了开始检验这一假设，进行了高通量筛选以鉴定IKKe抑制剂。发现的最有效和最特异的抑制剂是氨来萨诺;一种较老的药物，最初在日本开发用于治疗哮喘和过敏性鼻炎，后来在美国用于口疮溃疡，但没有很好的作用机制。它自1987年以来一直在使用，并具有良好的副作用。我们实验室获得的啮齿动物数据非常有希望，显示出令人兴奋的代谢效应，胰岛素抵抗、葡萄糖和脂质代谢沿着改善，肝脏脂肪变性改善，能量消耗增加。我们现在提出了一项早期概念验证临床研究，以转化我们在人体中使用氨来萨诺的实验室观察结果，具有3个特定目的：1）测试在改善肥胖2型糖尿病患者葡萄糖和胰岛素抵抗参数方面的代谢功效。2)检测其改善肝脏脂肪变性的疗效。3)开发氨来诺治疗2型糖尿病的生物标志物。如果成功的话，这一提议可能会为威胁数千万美国人的不断增长的代谢紊乱开辟一条新的治疗途径。

DESCRIPTION (provided by applicant): This proposal focuses on a clinical proof of concept study to evaluate a novel hypothesis. We hypothesize that the noncanonical Ikb kinases IKKe and TBK1 are "counterinflammatory" kinases that keep inflammatory pathways in check while helping to support a positive energy balance. Therefore, inhibition of this pathway selectively wil improve positive energy balance and insulin resistance supported by inflammation. In an effort to begin to test this hypothesis, a high-throughput screen was carried out to identify IKKe inhibitors. The most potent and specific inhibitor discovered was Amlexanox; an older drug originally developed in Japan for the treatment of asthma and allergic rhinitis, and later in the US for aphthous ulcers, but without a well understood mechanism of action. It has been in use since 1987, and has a favorable side effect profile. Rodent data obtained in our laboratory has been very promising, showing exciting metabolic effects with amelioration of insulin resistance, glucose and lipid metabolism along with improvement in hepatic steatosis and an increase in energy expenditure. We now propose an early proof-of concept clinical study to translate our laboratory observations using Amlexanox in humans with 3 specific aims: 1) to test the metabolic efficacy in improvement of glucose and insulin resistance parameters in obese Type 2 diabetics. 2) To test the efficacy on amelioration of hepatic steatosis. 3) To develop biomarkers for treatment of patients with type 2 diabetes by Amlexanox. If successful, this proposal may open the door to a novel treatment pathway for the ever-growing metabolic disturbances that are threatening tens of millions of Americans.