ERRgamma Agonists to Treat Muscular Dystrophy

ERRgamma 激动剂治疗肌营养不良症

• 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
• 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

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、亲脂性维生素和 大约一半的 NR 被归类为孤儿受体，因为它们确实如此。 没有明确表征的配体，因此，大量 NR 没有经过验证的化学工具。 考虑到几乎所有受体的体内功能，这是一个至关重要的需求。 已确定配体的 NR 是开发治疗药物的明确目标 多种疾病，包括癌症、糖尿病、动脉粥样硬化、炎症等 雌激素相关的孤儿受体与内分泌/生殖障碍有关。 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、血管化、 因此，针对这些受体的合成配体可能在治疗炎症和耳聋方面有用。 治疗多种人类疾病，包括肥胖症、2 型糖尿病、心血管疾病 （动脉粥样硬化）、癌症、骨质疏松症、炎症和耳聋。 体内活性有限的一流 ERRγ 激动剂在这里，我们描述了我们的计划。 优化 ERRγ 合成激动剂作为化学工具来探测这些激动剂的功能 体内受体以及确定靶向该受体治疗以下疾病的潜在效用 与骨骼肌功能障碍相关的疾病，特别是肌营养不良症。