Dual Targeting Mitochondria and GPCR in Retinal Protection

双靶向线粒体和 GPCR 在视网膜保护中的作用

基本信息

批准号：
10383538
负责人：
John D Ash
金额：
$ 25.57万
依托单位：
ARGOS VISION INC.
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：
2022-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10383538
关键词：
Address Adrenergic Receptor Age related macular degeneration Animals Biogenesis Blindness Caring Cellular biology Clinical Trials Complex Cone DNA Sequence Alteration Degenerative Disorder Development Disease Drug Targeting Environment Environmental Risk Factor Equipment Event Eye Development FDA approved Florida G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Genetic Genetic Models Health Technology Human Illinois Incubators Inflammation Inherited Intellectual Property Intervention Knowledge Legal patent Light Medical Medical Device Mitochondria Mitochondrial Proteins NADPH Oxidase Nerve Degeneration Outcome Oxidative Stress Pathogenicity Pathway interactions Pharmaceutical Preparations Pharmacotherapy Photoreceptors Plant Roots Process Regulation Research Research Personnel Resources Retina Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rod Safety Scientist Signal Transduction Structure Structure of retinal pigment epithelium Testing Therapeutic Time United States Universities Vision Visual impairment Work antioxidant therapy cost design drug discovery drug market effective therapy efficacy clinical trial efficacy evaluation environmental stressor experience genetic risk factor improved in vivo innovation light effects mitochondrial dysfunction mitochondrial metabolism mouse model novel novel therapeutic intervention oxidative damage photoreceptor degeneration preservation prevent small molecule therapeutic evaluation therapy development treatment effect

项目摘要

PROJECT SUMMARY Treatment for retinal degeneration that deteriorates photoreceptors and retinal pigment epithelium (RPE) cells remains limited to date. A significant challenge for therapeutic design in retinal protection is the complexity of degenerative mechanism. Single target intervention would not be effective to slow down or modify the degenerative course due to compensatory mechanisms of disease-related pathways. Multi-target intervention is increasingly important for effective treatment of complex disease including neurodegeneration. However, compounds with bioactivity that can intervene more than one disease-related pathways in retinal degeneration have not been explored. In this proposal, we will conduct in vivo therapeutic testing of a multi-target drug (CM- 20) in retinal protection via dual targeting both mitochondria and a G-protein coupled receptor (GPCR) to improve mitochondrial function and biogenesis and to mitigate retinal oxidative damage. Two mouse models of retinal degeneration will be used. One is an environmental stressor-induced retinal degeneration, and the other one is a genetic model of inherited retinal disease. We will evaluate efficacy of CM-20 in protecting outer retina and mitochondria and in reducing retinal oxidative stress. Positive outcomes would justify efficacy clinical trial in human retinal degeneration and provide mechanistic knowledge in mechanism of action.

项目摘要视网膜变性的治疗，可恶化感光体和视网膜色素上皮（RPE）细胞到目前为止仍然有限。视网膜保护方面的治疗设计的重大挑战是复杂性退化机制。单个目标干预不会有效减慢或修改由于疾病相关途径的补偿机制而导致的退化过程。多目标干预是对于包括神经变性在内的复杂疾病的有效治疗越来越重要。然而，具有生物活性的化合物，可以干预视网膜变性多种与疾病相关的途径尚未探索。在此提案中，我们将对多靶药进行体内治疗测试（CM- 20）通过双重靶向线粒体和G蛋白耦合受体（GPCR）进行视网膜保护，以改善线粒体功能和生物发生，并减轻视网膜氧化损伤。两种视网膜的小鼠模型将使用变性。一个是环境压力诱导的视网膜变性，另一个是遗传性视网膜疾病的遗传模型。我们将评估CM-20在保护外视网膜和线粒体和减少视网膜氧化应激。积极结果将证明有效性临床试验合理人类视网膜变性并提供作用机理的机械知识。