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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要