Novel Mitochondrial Targeted Neuroprotectants for Glaucoma

描述(申请人提供)：视神经疾病是不可逆性失明的常见原因。大多数都是无法治愈的，或者在确诊时导致永久性视力丧失。青光眼是一个例外，这是最常见的视神经疾病，其中最重要的危险因素是眼压升高。青光眼的治疗，目前仅限于药物或手术来降低眼压，往往无效。几乎所有其他视神经疾病都没有有效的治疗方法，包括缺血性视神经疾病(老年人最常见的急性视神经疾病)，视神经炎(年轻人最常见的急性视神经疾病)，以及许多其他疾病。视神经疾病中的视力丧失是由视网膜神经节细胞(RGC)选择性死亡引起的，RGC是通过视神经中的轴突将视觉信息从视网膜传递到大脑的神经元。几乎所有的视神经疾病都有一个共同的初始损伤，即RGC轴突的损伤，这触发了这些神经元的死亡。由于RGCs是中枢神经系统神经元，它们在高等生物体中的丢失是不可逆转的。这项提案的总体目标是通过专注于一种新的合成分子家族来调节细胞内活性氧物种(ROS)的水平，以找到预防或延缓视神经疾病导致的视力丧失的创新方法。我们最近证明，这些分子直接干扰RGC在轴突切断后的死亡。具体地说，我们计划：1.生产受保护的膦衍生物，经修饰后可穿透细胞膜，作为前体药物，并靶向视网膜节细胞。2.采用体外和体内生物测定方法鉴定铅神经保护化合物，包括视神经损伤所致的培养RGC死亡、视神经损伤所致的RGC死亡和高眼压所致的RGC死亡。拟议的研究将利用一个多学科合作团队，其中包括Pi在急性视神经疾病和RGC死亡信号方面的专业知识，合作研究员Di Polo在RGC生存信号和Morrison青光眼模型方面的专业知识，以及合作者Raines在合成与该项目相关的特定分子方面的专业知识。我们的长期目标是在培养和临床前动物模型中找到保护视神经的新的药理策略，希望确定可能导致临床试验的先导化合物，否则无法治疗的卵巢神经病。

DESCRIPTION (provided by applicant): Optic nerve diseases are common causes of irreversible blindness. Most are incurable or result in permanent visual loss by the time of diagnosis. An exception is glaucoma, the most common optic neuropathy, where the most important risk factor is elevated intraocular pressure. Treatments for glaucoma, currently limited to drugs or surgery to lower intraocular pressure, are often ineffective. Virtually all other optic neuropathies have no effective treatment, including ischemic optic neuropathy (the most common acute optic neuropathy of the elderly), optic neuritis (the most common acute optic neuropathy of the young), and many others. Loss of vision in optic neuropathies is caused by the selective death of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain via their axons in the optic nerve. Nearly all optic neuropathies have in common an initial injury to RGC axons, which triggers the death of these neurons. Because RGCs are central nervous system neurons, their loss is irreversible in higher organisms. The overall goal of this proposal is to find innovative ways to prevent or delay visual loss from optic nerve disease by focusing on a novel family of synthetic molecules that regulate intracellular levels of reactive oxygen species (ROS). We have recently demonstrated that these molecules directly interfere with RGC death after axotomy. Specifically, we plan to: 1. Produce protected phosphine derivatives modified to cross cell membranes, act as prodrugs, and target RGCs. 2. Use in vitro and in vivo bioassays to identify lead neuroprotective compounds, including axotomy- induced RGC death in culture, RGC death induced by optic nerve crush in vivo, and ocular hypertension-induced RGC death. The proposed studies will take advantage of a multidisciplinary collaborative team, with Pi's expertise in acute optic neuropathies and the signaling of RGC death, co-investigator Di Polo's expertise in RGC survival signaling and the Morrison glaucoma model, and collaborator Raines's expertise in synthesizing the specific molecules relevant to this project. Our long-term goal is to identify novel pharmacological strategies to protect the optic nerve in culture and pre-clinical animal models, with the hope of identifying lead compounds that could lead to clinical trials for otherwise untreatable ootic neuropathies.