Novel Therapy for Protection against Diabetes and its Complications in Ischemic Heart Disease

预防糖尿病及其缺血性心脏病并发症的新疗法

• 批准号: 10330933
• 负责人: Anindita Das
• 金额: $ 37.5万
• 依托单位: NOVOMEDIX, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330933
• 关键词: Accounting; Adult; Agonist; Animals; Atherosclerosis; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cessation of life; Chronic; Collagen; Conscious; Development; Diabetes Mellitus; Diabetic mouse; Disease Progression; Event; FRAP1 gene; Fibroblasts; Fibrosis; Future; Genes; Glucose; Goals; Healthcare; Heart; Heart Hypertrophy; Heart failure; Human; Hyperglycemia; Hypertrophy; Impairment; In Vitro; Individual; Inflammasome; Inflammation; Injury; Insulin; Insulin Resistance; Interleukin-11; Ischemia; Lead; Lipids; Liver Fibrosis; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocarditis; Myofibroblast; Non-Insulin-Dependent Diabetes Mellitus; Oral; Oryctolagus cuniculus; Outcome; Oxidative Stress; Pathologic; Patients; Pharmaceutical Preparations; Phase; Play; Population; Prevalence; Production; Pulmonary Fibrosis; Rattus; Reperfusion Injury; Reperfusion Therapy; Role; Serum; Severities; Signal Transduction; Stimulus; Testing; Time; Toxic effect; Toxicology; Transforming Growth Factor beta; Up-Regulation; Ventricular; blood glucose regulation; cardiometabolism; cardioprotection; clinically relevant; commercialization; coronary fibrosis; db/db mouse; diabetic; diabetic cardiomyopathy; diabetic patient; disability; effective therapy; heart function; hospital readmission; improved; in vivo; inhibitor/antagonist; interstitial; ischemic injury; mitochondrial dysfunction; mortality; mouse model; non-diabetic; novel; novel therapeutic intervention; novel therapeutics; pressure; prevent; programs; response; scale up

Abstract The overall goal of this program is the development and commercialization of a novel, safe, and effective therapy for diabetic cardiovascular disease (dCVD). The worldwide prevalence of diabetes has risen from 108 million in 1980 to 422 million in 2014 and is expected to increase to 700 million by 2045. Ninety percent of those with diabetes have type 2 diabetes (T2D), and 35% of those with T2D have cardiac dysfunction. Those with T2D are 2-3 times more likely to develop dCVD. Cardiovascular complications due to hyperglycemia, especially myocardial infarction and heart failure, are the leading cause of T2D-related morbidity and mortality, accounting for 68% of all diabetic deaths. NovoMedix has developed safe, first-in-class, oral drugs that have the potential to prevent dCVD and significantly improve long term outcomes for those with T2D by activating AMPK, inhibiting mTOR, preventing activation of the inflammasome, and inhibiting secretion of IL-11. We, therefore, seek to demonstrate that Novomedix’s leading compound (NMLC) is cardioprotective in diabetic mice and provides protection against myocardial infarction following ischemia/reperfusion (I/R) injury. NMLC is an allosteric AMPK agonist, an independent specific inhibitor of mTORC1 and an inhibitor of IL-11 secretion that prevents heart failure in a mouse TAC model and decreases fibrosis and inflammation in liver and lung fibrosis models in mice. NMLC should reduce/reverse disease progression in dCVD by: 1) improving lipid and glucose homeostasis by activating AMPK; 2) reducing oxidative stress, inhibiting the production of ROS, and reducing inflammation by inhibition of the NLRP3 inflammasome and activation of AMPK; and 3) providing cardioprotection against I/R injury by activating AMPK and independently inhibiting mTOR, and 4) preventing post-I/R cardiac fibrosis by inhibition of IL-11 and mTOR and activation of AMPK. Dr. Das and Dr. Salloum (VCU) recently tested NMLC in diabetic mice and in isolated diabetic mouse adult ventricular cardiomyocytes. NMLC improved metabolic parameters in diabetic mice and protected cardiomyocytes (isolated from diabetic mice) following simulated ischemia/reoxygenation (SI/RO) injury. As a result of the unique potential of this drug to protect the heart against I/R injury in diabetic condition, we propose the following specific aims: 1) confirm NMLC mechanism of cardioprotection in vitro, assess inhibition of IL-11 in cardiac fibroblasts, assess AMPK/mTOR signaling in human cardiomyocytes in an SI/RO model with high glucose, and scale up NMLC for in vivo studies; 2) examine the cardiometabolic impact of NMLC in a mouse model of T2D, determine the effect of NMLC on metabolism and diabetes-induced changes in cardiac function, and confirm mechanism of cardioprotection of NMLC in vivo; and 3) determine the beneficial effect of NMLC in the post-myocardial infarction in db/db mice, determine the effect of NMLC on myocardial infarct and fibrosis after I/R injury, and confirm mechanism of cardioprotection of NMLC in the post-ischemic heart.

抽象的 该计划的总体目标是一种新颖，安全和有效的开发和商业化 糖尿病心脏疾病的治疗（DCVD）。 1980年，2014年在1980年达到4.22亿，到2045年曝光至7亿。 患有糖尿病的人患有2型糖尿病（T2D） T2D由于高血糖而产生的DCVD的可能性高2-3倍。 特别是心肌梗塞和心力衰竭，是与T2D相关的发病率和死亡率的主要原因， 占所有糖尿病死亡的68％。 Novomedix已经开发了安全的，一流的口服药物，可以预防DCVD和 通过激活AMPK，抑制MTOR，预防，可以显着改善T2D患者的长期结局 因此，炎症体的激活和抑制IL-11的分泌。 Novomedix的主要化合物（NMLC）在糖尿病小鼠中具有心脏保护作用，并提供了防止 局部缺血/再灌注（I/R）损伤后心肌梗塞。 MTORC1的独立特异性抑制剂和IL-11分泌的吸入剂是心力衰竭 小鼠TAC模型并减少NMLC的肝脏和肺纤维化模型的纤维化和炎症 应减少DCVD中的/反向疾病进展：1）通过 激活AMPK； 2）减少氧化应激，遗传ROS的产生，并通过 抑制NLRP3炎症体和AMPK的激活； 3） 通过激活AMPK和独立侵害MTOR的伤害，以及4）防止I/R后心脏纤维化。 抑制IL-11和MTOR和AMPK的激活。 在糖尿病小鼠和孤立的糖尿病性室心肌细胞中 模拟后，糖尿病小鼠和受保护的心肌细胞的参数（从糖尿病小鼠中分离） 缺血/重氧（SI/RO）损伤。 作为时间的独特潜力 提出以下具体目的：1）在体外确认NMLC的NMLC机制，评估抑制作用 心脏成纤维细胞中的IL-11，评估Si/RO模型中人类心肌细胞中的AMPK/MTOR信号传导 使用高葡萄糖，并扩大NMLC的体内研究； 2）检查NMLC的心脏代谢影响 T2D的小鼠模型，确定NMLC对代谢和糖尿病诱导心脏变化的影响 功能，并确认NMLC在体内的心脏保护机制； 3） DB/DB小鼠的腰椎后梗死中的NMLC，确定NMLC对心肌梗死和 I/R损伤后的纤维化，并确认缺血后心脏中NMLC心脏保护的机制。