Targeting Diabetes With Novel SERCA Allosteric Activators

利用新型 SERCA 变构激活剂治疗糖尿病

基本信息

批准号：
10573471
负责人：
DJAMEL LEBECHE
金额：
$ 34.65万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-16 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10573471
关键词：
Address Agonist Animal Model Animals Apoptosis Beta Cell Biological Assay Blood Glucose Ca(2+)-Transporting ATPase Calcium Cell Death Cell Survival Cell physiology Cells Chemicals Clinical Cultured Cells Data Defect Development Diabetes Mellitus Disease Endoplasmic Reticulum Enzymes Epidemic Equilibrium Fatty Liver Functional disorder Genetic Models Glucose Goals Health Hepatocyte High Fat Diet Homeostasis Human Hyperglycemia Hypoglycemia Impairment In Vitro Incidence Insulin Insulin Resistance Knockout Mice Knowledge Lead Mediating Medical Metabolic Metabolic Diseases Metabolic Pathway Metabolism Mitochondria Modality Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Outcome Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiological Property Pump Series Societies Specificity Testing Therapeutic Thinness Toxic effect analog animal data base biological adaptation to stress cell injury design diabetes mellitus therapy diabetic endoplasmic reticulum stress experimental study glucose metabolism glucose tolerance improved in vitro Assay in vivo innovation insulin secretion insulin sensitivity lead series liver metabolism loss of function novel novel strategies preservation scaffold small molecule therapy development translational applications translational potential uptake

项目摘要

Obesity and insulin resistance are major causes of type 2 diabetes, representing an enormous health burden to societies worldwide. Major perturbations associated with diabetes are abnormalities in calcium homeostasis and substrate metabolism, and induction of insulin resistance. Interestingly, disruption of endoplasmic reticulum (ER) Ca2+ levels caused primarily by impaired function of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) has been demonstrated to trigger ER stress in liver and β cell leading to the development of insulin resistance in obesity and diabetes conditions. Thus, targeting dysfunctional SERCA2 will alleviate aberrant ER stress and associated disorders in diabetes. We pharmacologically activated SERCA2b in a genetic model of insulin resistance and type 2 diabetes (ob/ob mice) with a novel class of small molecules that allosterically activate SERCA enzyme and rescue ER stress-induced cell death. These compounds are amenable to optimization for potency, and have enormous potential to treat diabetes. Studies in animal models of diabetes show significant improvement in glucose tolerance, hepatic steatosis and metabolism, and preservation of β-cell function and survival. Through medicinal chemistry and analoging strategies, we aim in this proposal to conduct compound optimization of these novel series of SERCA activators and profile them more extensively in vitro and in vivo for further development as SERCA-based therapeutic modalities to treat diabetes and its complications.

肥胖和胰岛素抵抗是 2 型糖尿病的主要原因与糖尿病相关的主要扰动是全世界社会的健康负担。钙稳态和底物代谢异常以及胰岛素诱导提示，内质网 (ER) Ca2+ 水平的破坏主要引起。由于肌浆/内质网 Ca2+-ATP 酶 (SERCA) 功能受损触发肝脏和 β 细胞的 ER 应激，从而导致胰岛素的产生因此，针对功能失调的 SERCA2 将会产生抵抗力。我们通过药物缓解了糖尿病患者的异常 ER 应激和相关疾病。在胰岛素抵抗和 2 型糖尿病遗传模型（ob/ob 小鼠）中激活 SERCA2b 含有一类新型小分子，可变构激活 SERCA 酶并拯救 ER 这些化合物可以优化效力，并且糖尿病动物模型研究表明，具有治疗糖尿病的巨大潜力。显着改善葡萄糖耐量、肝脏脂肪变性和代谢，以及通过药物化学和模拟来保存 β 细胞功能和存活。策略，我们的目标是在这个提案中对这些新颖的系列进行复合优化 SERCA 激活剂并主要在体外和体内对其进行分析以供进一步开发作为基于 SERCA 的治疗方式来治疗糖尿病及其并发症。