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ERRgamma Agonists to Treat Muscular Dystrophy

ERRgamma 激动剂治疗肌营养不良症

基本信息

批准号：
9176946
负责人：
Thomas P Burris
金额：
$ 58.07万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9176946
关键词：
Address Adipose tissue Affinity Agonist Animals Area Atherosclerosis Binding Bone Resorption Cardiovascular Diseases Cell Proliferation Chemicals Cholesterol DNA Development Diabetes Mellitus Disease Drug Kinetics Duchenne muscular dystrophy Endocrine Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Evaluation Functional disorder Goals Heart Human Inflammation Kidney Ligand Binding Ligands Liver Malignant Neoplasms Mitochondria Modeling Muscle Fibers Muscle function Muscular Dystrophies Names Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obesity Orphan Osteogenesis Osteoporosis Pattern Physiological Processes Property Research Response Elements Scheme Skeletal Muscle Stomach Structure-Activity Relationship Thyroid Hormones Tissues Vascularization Vitamins Work deafness drug development estrogen-related receptor glucose metabolism human disease in vivo lipid metabolism monomer novel receptor receptor function reproductive skeletal muscle metabolism steroid hormone receptor tool transcription factor

项目摘要

The nuclear receptor (NR) superfamily constitutes a group of 48 transcription factors in humans, which includes the receptors for steroid hormones, thyroid hormone, lipophilic vitamins, and cholesterol metabolites. Approximately half of NRs are classified as orphan receptors since they do not have well characterized ligands. Thus, a large number of NRs have no validated chemical tools to use to probe the function of these receptors in vivo. This is a critical need given that virtually all the NRs that have identified ligands are well-characterized targets for the development of drugs to treat myriad diseases including cancer, diabetes, atherosclerosis, inflammation, and endocrine/reproductive disorders. The estrogen-related orphan receptors have been implicated in a range of physiological processes including lipid and glucose metabolism, mitochondrial function, cellular proliferation/cancer, bone formation, muscle fiber type determination, vascularization, inflammation and deafness. Thus, synthetic ligands targeting these receptors may hold utility in treatment of myriad human disorders including obesity and type 2 diabetes, cardiovascular disease (atherosclerosis), cancer, osteoporosis, inflammation, and deafness. We have developed a novel, first-in-class ERRγ agonist that display limited in vivo activity. Here, we describe our plans for optimization of ERRγ synthetic agonists for use as chemical tools to probe the function of these receptors in vivo as well as to determine potential utility of targeting this receptor for treatment of diseases associated with skeletal muscle dysfunction, in particular muscular dystrophy.

核受体（NR）超家族由48个转录因子组成，人类，包括类固醇激素、甲状腺激素、亲脂性维生素的受体，胆固醇代谢物。大约一半的NR被归类为孤儿受体，因为它们没有很好地表征配体。因此，许多国家代表没有经过验证的化学工具来探测这些受体在体内的功能。这是一个关键的需要，因为几乎所有的已经鉴定出配体的NR是用于开发药物以治疗癌症的良好表征的靶标。包括癌症、糖尿病、动脉粥样硬化、炎症和内分泌/生殖失调。雌激素相关的孤儿受体与一种一系列生理过程，包括脂质和葡萄糖代谢，线粒体功能，细胞增殖/癌症，骨形成，肌纤维类型测定，血管形成，炎症和耳聋。因此，靶向这些受体的合成配体可以在免疫治疗中保持效用。治疗包括肥胖和2型糖尿病、心血管疾病在内的多种人类疾病（动脉粥样硬化）、癌症、骨质疏松症、炎症和耳聋。我们开发了一部小说，第一类ERRγ激动剂，其显示有限的体内活性。在这里，我们描述了我们的计划，优化ERRγ合成激动剂，用作化学工具来探测这些受体的功能。以及确定靶向该受体用于治疗以下疾病的潜在效用与骨骼肌功能障碍相关的疾病，特别是肌营养不良。