权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting Diabetes With Novel Small Molecule Therapeutics

用新型小分子疗法治疗糖尿病

基本信息

批准号：
9001399
负责人：
DJAMEL LEBECHE
金额：
$ 16.95万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2016-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9001399
关键词：
ATP2A2 Address Agonist Animal Model Animals Apoptosis Beta Cell Biological Assay Blood Glucose Ca(2+)-Transporting ATPase Calcium Cause of Death Cell Death Cell Survival Cells Clinical Cultured Cells Data Dependovirus Developed Countries Development Diabetes Mellitus Diabetic mouse Disease Endoplasmic Reticulum Enzymes Fatty Liver Fatty acid glycerol esters Functional disorder Gene Transfer Glucose Goals Health Hepatocyte Homeostasis Hyperglycemia Hypoglycemia Incidence Insulin Insulin Resistance Knowledge Liver Medical Metabolic Metabolic Diseases Metabolism Methodology Mitochondria Modality Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Outcome Pharmaceutical Preparations Physiological Play Property Pump Role Series Serotyping Societies Specificity Testing Therapeutic Toxic effect Translating Up-Regulation Work base biological adaptation to stress blood glucose regulation design diabetic drug development endoplasmic reticulum stress gene therapy genetic manipulation glucose tolerance improved in vitro testing in vivo in vivo Model innovation insulin secretion insulin sensitivity loss of function member non-diabetic novel novel strategies novel therapeutics research study screening small molecule therapy development uptake

项目摘要

DESCRIPTION (provided by applicant): Obesity and insulin resistance are major causes of type 2 diabetes, which represents an enormous health burden to societies worldwide and is the fourth leading cause of death in most developed countries. 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 has been demonstrated to trigger ER stress leading to the development of insulin resistance in obesity and diabetes conditions. A major cause of ER stress is disturbed calcium homeostasis caused by dysfunctional sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). In fact, SERCA2b activity and expression is diminished in animal models of obesity/diabetes. Upregulation of SERCA in liver of obese and diabetic mice via short term gene transfer reduced ER stress and improved glucose homeostasis. Thus, targeting dysfunctional SERCA2 pharmacologically will alleviate aberrant ER stress and associated disorders in diabetes. Using novel screening methodology, we have discovered a series of novel, drug-like small molecules that activate SERCA and rescue ER stress-induced cell death, are amenable to optimization for potency, and have enormous potential to treat diabetes. Preliminary results in animal models of diabetes show significant improvement in glucose tolerance, insulin sensitivity, hepatic steatosis and metabolism. In this proposal, we aim to conduct compound optimization of our novel series of allosteric SERCA activators and profile them more extensively to observe efficacy in in vivo models of diabetes, and to demonstrate that these novel SERCA activators rescue ER stress, improve glucose tolerance and restore insulin sensitivity. Our goal is to provide drug-like compounds suitable for development as novel therapeutic potential to treat diabetes.