Dual Targeting Mitochondria and GPCR in Retinal Protection

项目总结 治疗恶化感光细胞和视网膜色素上皮(RPE)细胞的视网膜变性 到目前为止仍然是有限的。视网膜保护治疗设计的一个重大挑战是 退化机制。单一目标干预将不会有效地减缓或修改 疾病相关途径的代偿机制导致的退变过程。多目标干预是 对包括神经变性在内的复杂疾病的有效治疗日益重要。然而， 具有生物活性的化合物可干预视网膜变性中多种疾病相关途径 还没有被探索过。在这项提案中，我们将对一种多靶点药物(CM- 20)通过双重靶向线粒体和G蛋白偶联受体(GPCR)来改善视网膜保护 线粒体功能和生物发生，并减轻视网膜氧化损伤。两种小鼠视网膜模型 将使用退化。一种是环境应激源引起的视网膜变性，另一种是 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。积极的结果将证明有效性临床试验是合理的 人类视网膜退化，并提供作用机制方面的机械知识。

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.