Development of Controlled Release Mitochondrial Protonophore (CRMP) as a Novel Treatment for Type-2 Diabetes and Non-Alcoholic Steatohepatitis in Dysmetabolic Non-Human Primates

开发控释线粒体原细胞 (CRMP) 作为代谢失调的非人类灵长类动物 2 型糖尿病和非酒精性脂肪性肝炎的新型治疗方法

• 批准号: 9894796
• 负责人: GERALD I SHULMAN
• 金额: $ 53.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894796
• 关键词: Acetyl Coenzyme A; Adipocytes; Affect; Behavior; Body Composition; Body Weight; Body Weight decreased; Caloric Restriction; Cell secretion; Chronic; Closure by clamp; Data; Development; Diacylglycerol Kinase; Diglycerides; Disease Resistance; Eating; Fatty Liver; Fatty acid glycerol esters; General Population; Generations; Gluconeogenesis; Glucose; Glucose Clamp; Glycerol; Grant; Hepatic; Human; Hypertriglyceridemia; Induced Hyperthermia; Insulin; Insulin Resistance; Lipids; Liquid Chromatography; Liver; Liver Fibrosis; Liver Mitochondria; Macaca mulatta; Measurement; Measures; Mediating; Metabolic; Metabolic syndrome; Methodology; Methods; Mitochondria; Modeling; Monitor; Monkeys; Muscle; NMR Spectroscopy; Non-Insulin-Dependent Diabetes Mellitus; Non-Rodent Model; Obesity; Oral; Palmitates; Pathogenesis; Placebos; Plasma; Predisposing Factor; Pyruvate Carboxylase; Pyruvate Kinase; Research; Rodent; Safety; Steatohepatitis; Structure of beta Cell of islet; Syndrome; Therapeutic Agents; Therapeutic Index; Tissues; Tracer; Triglycerides; Uncoupling Agents; base; ceramide kinase; clinically relevant; cohort; controlled release; cytokine; design; fatty acid oxidation; global health; glucose production; human model; improved; insulin sensitivity; intravenous glucose tolerance test; ketogenesis; liver biopsy; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; nonhuman primate; novel; novel drug class; novel therapeutics; oxidation; protein activation; protein kinase C epsilon; pyruvate dehydrogenase; side effect; stable isotope; success; systemic toxicity; tandem mass spectrometry; treatment strategy

Non-alcoholic fatty liver disease (NAFLD) is estimated to occur in one third of the general population and is a major predisposing factor in the pathogenesis of hepatic insulin resistance and type 2 diabetes (T2D). NAFLD occurs when lipid supply to the liver exceeds rates of lipid oxidation and lipid export. A number of therapies have been employed to reduce ectopic-fat accumulation in liver and hepatic insulin resistance, however these approaches have been met with limited success in the long-term and new therapies are required. In order to meet this great unmet need, our lab has recently developed a Controlled Release Mitochondrial Protonophore (CRMP) that is functionally liver-targeted and causes increased mitochondrial fat oxidation by promoting a subtle sustained increase in hepatic mitochondrial uncoupling activity. Importantly, we have previously demonstrated that CRMP safely reverses hypertriglyceridemia, fatty liver, steatohepatitis and liver fibrosis in rodent models of NAFLD/NASH/liver fibrosis and T2D without inducing hyperthermia, weight loss or any associated hepatic/systemic toxicities. Taken together, these rodent studies provide important proof of concept for the further assessment of CRMP as a novel therapeutic strategy for the treatment of NAFLD/NASH and T2D in a highly relevant non-human primate model of NAFLD and the dysmetabolic syndrome. Therefore, in the present proposal, we aim to determine the safety and efficacy of chronic CRMP treatment on the reversal of hypertriglyceridemia, NAFLD, and liver and muscle insulin resistance in dysmetabolic, spontaneously obese Rhesus monkeys. In addition, we will perform a comprehensive set of hepatic metabolic flux measurements using state-of-the-art liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance spectroscopy methods to directly assess the impact of chronic CRMP treatment on rates of hepatic mitochondrial fatty acid oxidation, gluconeogenesis, pyruvate dehydrogenase flux, pyruvate kinase flux and hepatic ketogenesis in this obese dysmetabolic monkey model of NAFLD. We hypothesize that chronic CRMP treatment will reverse NAFLD and improve whole-body insulin responsiveness in obese dysmetabolic Rhesus monkeys in a safe and effective manner by promoting increased rates of hepatic mitochondrial fatty acid oxidation independent of changes in food intake/body weight. Collectively, the results of this research will be highly impactful in that they will provide important proof-of-concept and safety data in a highly relevant clinical model of obese dysmetabolic non-human primates to support the development of novel liver-targeted mitochondrial uncoupling agents for the treatment of NAFLD/NASH and T2D in humans.

估计非酒精性脂肪肝病（NAFLD）发生在一般人群的三分之一，是肝胰岛素抵抗和2型糖尿病（T2D）发病机理的主要诱发因素。当脂质供应肝脏超过脂质氧化和脂质出口速率时，就会发生NAFLD。已经采用了许多疗法来减少肝脏和肝胰岛素抵抗中的异位脂肪积累，但是这些方法在长期的成功中取得了有限的成功，需要新的疗法。为了满足这一巨大的需求，我们的实验室最近开发了受控的线粒体质子团（CRMP），该线粒体在功能上是肝脏靶向的，并通过促进肝线粒体脉冲脉冲的细微持续增加而导致线粒体脂肪氧化增加。重要的是，我们以前已经证明，在NAFLD/NASH/NASH/LIVER纤维化的啮齿动物模型中，CRMP可以安全地逆转高糖性血症，脂肪肝脏，脂肪性肝炎和肝纤维化，而无需诱导高温，体重减轻或任何相关的肝/系统毒性。综上所述，这些啮齿动物研究为进一步评估CRMP作为一种新型的治疗策略提供了重要的概念证明，用于在高度相关的NAFLD和DYSMATEMMATEBOLIC综合征中对NAFLD/NASH和T2D进行治疗。因此，在本提案中，我们旨在确定慢性CRMP治疗对高甘油三酸酯，NAFLD，NAFLD以及肝脏和肌肉胰岛素耐药性逆转的安全性和功效。此外，我们将使用最先进的液态色谱量表质谱法和核磁共振光谱法直接评估慢性CRMP治疗对肝脂肪酸氧化，葡萄糖迅速爆炸，脱氧于KIN的肝脏氧化，脱氧于型肝氧化速率，脱氧于KIN的速率，使用液态色谱和核磁共振光谱法进行全面的肝代谢通量测量。在这个肥胖的NAFLD肥胖糖猴模型中。我们假设慢性CRMP治疗将逆转NAFLD，并通过促进肝线粒体脂肪酸氧化的速度增加，而与食物摄入/体重的变化无关，以安全有效的方式改善了肥胖的疾病代谢恒河猴在肥胖的疾病代谢恒河猴中的全身反应。总的来说，这项研究的结果将具有很高的影响力，因为它们将在高度相关的肥胖异代代谢非人类灵长类动物的临床模型中提供重要的概念证明和安全数据，以支持新型肝脏靶向的线粒体解偶联剂的开发，以治疗人类的NAFLD/NASH和T2D。