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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，代表了巨大的