Preclinical validation of ABHD5 as a target for treatment of obesity.

ABHD5 作为肥胖治疗靶点的临床前验证。

基本信息

批准号：
9114105
负责人：
James G Granneman
金额：
$ 69.55万
依托单位：
WAYNE STATE UNIVERSITY
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：
2015-07-21 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9114105
关键词：
Acute Adipocytes Adipose tissue Adrenergic Agonists Adrenergic Receptor Agonist Animal Model Binding Burn injury Bypass Chemicals Chronic Clinical Cyclic AMP Cyclic AMP-Dependent Protein Kinases Development Diabetes Mellitus Diet Disease Drug Kinetics Energy Metabolism Fatty Acids Fatty acid glycerol esters Gene Expression Genetic Models Goals Health Human In Situ In Vitro Insulin Isoproterenol Lead Libraries Ligand Binding Lipase Lipids Lipolysis Metabolism Molecular Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated disease Pharmaceutical Chemistry Physiological Pre-Clinical Model Proteins Scaffolding Protein Series Signal Transduction Staging Structure Sum Therapeutic Therapeutic Effect Thermogenesis Tissues Toxic effect Treatment Efficacy United States National Institutes of Health Validation Work base experience fatty acid oxidation improved in vivo insight novel obesity treatment overexpression oxidation pre-clinical prevent receptor research study scaffold screening therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The accumulation of toxic lipids in non-adipose tissues, termed lipotoxicity, is a major means by which obesity produces disease. One therapeutic approach to obesity-related disease, including type 2 diabetes, is to expand the ability of adipose tissues to mobilize and burn fatty acids in situ and thereby prevent lipotoxic lipid accumulation elsewhere. Preclinical experience with β3-adrenergic agonists and lipase overexpression in adipose tissue indicates that activation of adipocyte lipolysis is sufficient to increase energy expenditure which reduces obesity and improves systemic metabolism. Recent discoveries suggested that adipocyte lipolysis and fat oxidation might be stimulated by agents that release ABHD5 from perilipin1 (PLIN1), and such compounds might be developed for treatment of obesity-related disorders. Screening of the NIH 360,000 compound library identified five such compounds, representing three distinct chemical scaffolds. Initial structure-activity relations experiments demonstrate that the chemical scaffolds are mechanism-based and amenable to chemical improvement. The overall goal of this project is to provide early stage pharmacological validation of the ABHD5/PLIN1 interaction as a therapeutic target for treatment of obesity and obesity-related disease.

描述（由适用提供）：被称为脂肪毒性的非脂肪组织中有毒脂质的积累是肥胖产生疾病的主要手段。肥胖相关疾病的一种治疗方法，包括2型糖尿病，是扩大脂肪组织动员和燃烧原位脂肪酸的能力，从而防止其他地方的脂肪毒性脂质积累。脂肪组织中β3-肾上腺素能激动剂和脂肪酶过表达的临床前经验表明，脂肪细胞脂肪解析的激活足以增加能量消耗，从而减少肥胖并改善系统性代谢。最近的发现表明，脂肪细胞脂解和脂肪氧化可能会受到从Perilipin1（PLIN1）（PLIN1）释放ABHD5的药物，并且可能开发出来用于治疗与肥胖相关疾病的治疗。 NIH 360,000化合物库的筛选确定了五种此类化合物，代表了三个不同的化学支架。最初的结构活性关系实验表明，化学支架是基于机制的，并且可用于化学改善。该项目的总体目标是提供ABHD5/PLIN1相互作用的早期药物验证，作为治疗肥胖和与肥胖相关疾病的治疗靶标。