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

描述(由申请人提供)：这项建议侧重于临床概念验证研究，以评估一个新的假设。我们假设，非规范的IKB激酶IKKE和TBK1是“抗炎”激酶，在帮助维持正能量平衡的同时，控制炎症途径。因此，选择性地抑制这一途径将改善正能量平衡和炎症支持的胰岛素抵抗。为了开始验证这一假说，进行了高通量筛选以确定IKKE抑制剂。被发现的最有效和最特异的抑制剂是氨来昔诺；这是一种最初在日本开发用于治疗哮喘和过敏性鼻炎的旧药，后来在美国开发用于治疗口疮，但没有很好的作用机制。它自1987年以来一直在使用，并有良好的副作用。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，改善了胰岛素抵抗、葡萄糖和脂肪代谢，改善了肝脏脂肪变性，增加了能量消耗。我们现在建议进行一项早期概念验证临床研究，将我们在人类中使用氨来昔诺的实验室观察转化为3个具体目标：1)测试改善肥胖2型糖尿病患者血糖和胰岛素抵抗参数的代谢有效性。2)检测其改善肝脏脂肪变性的疗效。3)开发氨来昔诺治疗2型糖尿病的生物标志物。如果成功，这项提议可能会为威胁数千万美国人的日益严重的代谢紊乱打开一条新的治疗途径的大门。

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.