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Mitochondrial K+ Channels as Anti-Obesity Drug Targets

线粒体 K 通道作为抗肥胖药物靶点

基本信息

批准号：
10242449
负责人：
Paul S Brookes
金额：
$ 19.25万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242449
关键词：
2,4-Dinitrophenol ATP Synthesis Pathway Adipose tissue Adult Agonist Anti-Obesity Agents Belief Biochemistry Blood Glucose Body fat Cell physiology Cells Chemicals Clinical Coupling Data Diabetes Mellitus Dinitrophenols Disease Dose-Limiting Drug Screening Drug Targeting Electron Transport Enzymes Epoxide hydrolase Equilibrium Exhibits Food Genes Genetic Polymorphism Genus Hippocampus Goals High Fat Diet Human Link Lipids Medical Membrane Metabolic Metabolic Diseases Metabolism Mitochondria Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Organelles Oxidative Phosphorylation Pathology Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Potassium Channel Preventive Process Property Proteins Public Health Reporting Research Research Personnel Risk Factors Runaway Testing Therapeutic Toxic effect Weight cohort combat diet and exercise drug efficacy drug synthesis drug testing effectiveness testing energy balance high throughput screening inhibitor/antagonist metabolic phenotype mitochondrial K(ATP) channel mitochondrial uncoupling protein mortality new therapeutic target nitazoxanide novel obesity treatment oligomycin sensitivity-conferring protein oxidation public health intervention side effect stem uncoupling protein 1

项目摘要

Despite public health intervention efforts, the global burden of metabolic diseases such as type-II diabetes continues to rise, and a major risk factor for such diseases is obesity. This project explores novel drug targets in mitochondria that can modulate whole-body energy balance, a key determinant of obesity. In mitochondrial energetics, coupling between fuel oxidation and ATP synthesis occurs via a trans-membrane H+ gradient, and the uncoupling of mitochondria to dissipate this H+ gradient as heat has long been viewed as a potential drug target to alter whole-body energy balance. However, direct chemical uncouplers (e.g., dinitrophenol) are plagued by fatal dose-limiting toxicity, and mitochondrial uncoupling proteins (UCPs) have not yet delivered on their initial promise as obesity drug targets. A potential uncoupling pathway that has been largely ignored is mitochondrial K+ channels, whose opening in concert with the mitochondrial K+/H+ exchanger could uncouple mitochondria. Recently we reported a Na+ activated K+ channel (KNa1.2, Kcnt2 gene) exists in mitochondria, and that KNa channel agonists can uncouple in wild-type (WT) but not Kcnt2-/- cells. In addition, Kcnt2-/- mice have elevated body fat and dysregulated blood glucose. They also gain more weight and exhibit more hepatosteatosis (vs. WT) on a high fat diet (HFD). Furthermore, recent reports of compounds exhibiting therapeutic benefits in HFD-fed mice, have overlooked that these compounds are KNa channel openers. Another K+ channel found in mitochondria is KCa1.1 (Kcnma1 gene), and notably Kcnma1-/- mice are obese and human Kcnma1 polymorphisms are linked to obesity. Certain reactive lipids can open KCa channels, including those in mitochondria, and inhibitors of soluble epoxide hydrolase (sEH, the enzyme that degrades these lipids) are beneficial against HFD-induced pathology. This suggests mitochondrial K+ channel uncoupling as a mechanism of action for such drugs. Overall, we hypothesize that mito-K+ channels represent a novel uncoupling pathway and potential anti-obesity drug target. Aim 1 will focus on mito-KNa1.2, aiming to develop novel mitochondria-targeted KNa agonists, to be screened using WT and Kcnt2-/- mice. Aim 2 focuses on mito-KCa1.1, testing drug efficacy in WT and Kcnma1-/- mice. Our goal is to develop mito-K+ agonists as a novel class of anti-obesity drugs.

尽管公共卫生干预努力，全球代谢性疾病（如ii型糖尿病）的负担仍在继续增加，而这类疾病的一个主要危险因素是肥胖。该项目探索线粒体中可以调节全身能量平衡的新药物靶点，这是肥胖的关键决定因素。在线粒体能量学中，燃料氧化和ATP合成之间的偶联是通过跨膜H+梯度发生的，而线粒体的解偶联以热量消散H+梯度一直被视为改变全身能量平衡的潜在药物靶点。然而，直接化学解偶联剂（如二硝基苯酚）受到致命的剂量限制毒性的困扰，线粒体解偶联蛋白（UCPs）尚未实现其最初作为减肥药靶点的承诺。一个潜在的解偶联途径是线粒体K+通道，它的打开与线粒体K+/H+交换器一致，可以解偶联线粒体。最近，我们报道了线粒体中存在一个Na+激活的K+通道（KNa1.2， Kcnt2基因），并且KNa通道激动剂可以在野生型（WT）中解偶，但不能在Kcnt2-/-细胞中解偶。此外，Kcnt2-/-小鼠体脂升高，血糖失调。在高脂肪饮食（HFD）中，他们也会增加更多的体重，并表现出更多的肝纤维化（与WT相比）。此外，最近关于化合物在hfd喂养的小鼠中显示出治疗益处的报道忽略了这些化合物是KNa通道打开剂。在线粒体中发现的另一个K+通道是KCa1.1 （Kcnma1基因），值得注意的是Kcnma1-/-小鼠肥胖，而人类Kcnma1多态性与肥胖有关。某些反应性脂质可以打开KCa通道，包括线粒体中的通道，可溶性环氧化物水解酶（sEH，降解这些脂质的酶）的抑制剂对hfd诱导的病理有益。这表明线粒体K+通道解偶联是这类药物的作用机制。总之，我们假设mito-K+通道代表了一种新的解偶联途径和潜在的抗肥胖药物靶点。目的1将集中于mitto - kna1.2，旨在开发新的线粒体靶向KNa激动剂，使用WT和kcn2 -/-小鼠进行筛选。目的2聚焦于mitto - kca1.1，检测WT和Kcnma1-/-小鼠的药物疗效。我们的目标是开发mito-K+激动剂作为一类新的抗肥胖药物。