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

探讨 r 中“抗炎”非经典 IkB 激酶的相关性

• 批准号: 8735137
• 负责人: Elif Arioglu Oral
• 金额: $ 19.16万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735137
• 关键词: Address; Adipose tissue; Adverse effects; Albumins; Allergic rhinitis; American; Aphthous Stomatitis; Asthma; Biochemistry; Biological Markers; Blood; Body Composition; Body Weight; Body Weight decreased; Chemicals; Chronic; Clinical; Clinical Markers; Clinical Research; DEXA; Data; Development; Dose; Double-Blind Method; Drug Kinetics; Drug Targeting; Energy Metabolism; Enrollment; Evaluation; Fasting; Fatty Liver; Fatty acid glycerol esters; Feedback; Future; Generations; Genes; Glucose; Glycosylated hemoglobin A; Human; Hyperglycemia; Indirect Calorimetry; Inflammation; Inflammatory; Insulin; Insulin Resistance; Japan; Laboratories; Lipids; Liver; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Metabolic; Metformin; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Oral; Organ; Participant; Paste substance; Pathway interactions; Patients; Pharmaceutical Preparations; Phospho-Specific Antibodies; Phosphorylation; Phosphotransferases; Placebos; Plasma; Play; Regulation; Rest; Rodent; Role; Safety; Serum; Stress; TBK1 gene; Tablets; Testing; Tissue Sample; Translating; Urine; Weight; Work; amlexanox; attenuation; design; diabetic; drug discovery; efficacy testing; energy balance; feeding; glucose metabolism; high throughput screening; human study; improved; inhibitor/antagonist; insulin secretion; insulin sensitivity; interest; lipid metabolism; liver inflammation; non-alcoholic fatty liver; novel; placebo controlled study; public health relevance; response; small molecule libraries; urinary

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.

描述（由申请人提供）：本提案侧重于临床证明的概念研究，以评估一个新的假设。我们假设非典型Ikb激酶IKKe和TBK1是“抗炎”激酶，在帮助支持正能量平衡的同时保持炎症途径。因此，选择性抑制这一途径将改善炎症支持的正能量平衡和胰岛素抵抗。为了开始验证这一假设，进行了高通量筛选以鉴定IKKe抑制剂。发现的最有效和特异性的抑制剂是氨lexanox；这是一种最早在日本开发的用于治疗哮喘和过敏性鼻炎的老药，后来在美国用于治疗阿弗顿溃疡，但没有一个很好的了解作用机制。自1987年以来，它一直在使用，并且具有良好的副作用。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作用，改善胰岛素抵抗，葡萄糖和脂质代谢，改善肝脂肪变性和增加能量消耗。我们现在提出一项早期概念验证临床研究，将我们的实验室观察结果转化为Amlexanox在人类身上的应用，有三个具体目的：1)测试肥胖2型糖尿病患者改善葡萄糖和胰岛素抵抗参数的代谢功效。2)观察其对肝脏脂肪变性的改善作用。3)开发Amlexanox治疗2型糖尿病患者的生物标志物。如果成功，这一提议可能会为不断增长的代谢紊乱打开一扇新的治疗途径的大门，这些紊乱正威胁着数千万美国人。