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Novel Mitochondrial Targeted Neuroprotectants for Glaucoma

新型线粒体靶向青光眼神经保护剂

基本信息

批准号：
7351810
负责人：
Leonard A Levin
金额：
$ 20.37万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7351810
关键词：
Acute Animal Model Axon Axotomy Blindness Boron Brain Cell Death Cell Survival Cell membrane Cessation of life Clinical Trials Data Diagnosis Elderly Family Glaucoma Goals In Vitro Injury Ischemic Optic Neuropathy Lead Mitochondria Modeling Nerve Crush Neuraxis Neurons Neuropathy Neuroprotective Agents Ocular Hypertension Operative Surgical Procedures Optic Nerve Optic Neuritis Organism Patients Pharmaceutical Preparations Phosphines Physiologic Intraocular Pressure Prodrugs Reactive Oxygen Species Research Personnel Retina Retinal Ganglion Cells Risk Factors Signal Pathway Signal Transduction Signal Transduction Pathway Specificity Sulfhydryl Compounds Superoxides Time Translations design in vivo in vivo Bioassay innovation multidisciplinary neuroprotection novel optic nerve disorder oxidation phosphine pre-clinical prevent tris(2-carboxyethyl)phosphine visual information

项目摘要

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.

描述（由申请人提供）：视神经疾病是不可逆失明的常见原因。大多数是无法治愈的，或者在诊断时导致永久性视力丧失。一个例外是青光眼，最常见的视神经病变，其中最重要的风险因素是眼内压升高。青光眼的治疗目前仅限于药物或手术来降低眼内压，通常无效。几乎所有其他视神经病变都没有有效的治疗方法，包括缺血性视神经病变（老年人最常见的急性视神经病变），视神经炎（年轻人最常见的急性视神经病变）等。视神经病变中的视力丧失是由视网膜神经节细胞（RGC）的选择性死亡引起的，视网膜神经节细胞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。几乎所有的视神经病变都有一个共同的RGC轴突的初始损伤，这会引发这些神经元的死亡。由于RGC是中枢神经系统神经元，它们的损失在高等生物中是不可逆的。该提案的总体目标是通过关注调节细胞内活性氧（ROS）水平的新型合成分子家族，找到预防或延迟视神经疾病所致视力丧失的创新方法。我们最近证明，这些分子直接干扰轴突切断后RGC的死亡。具体而言，我们计划：1。产生经修饰以穿过细胞膜的受保护膦衍生物，作为前药并靶向RGC。2.使用体外和体内生物测定来鉴定主要神经保护化合物，包括轴突切断诱导的培养物中RGC死亡、体内视神经挤压诱导的RGC死亡以及高眼压诱导的RGC死亡。拟议的研究将利用一个多学科的合作团队，Pi在急性视神经病变和RGC死亡信号方面的专业知识，共同研究者Di波罗在RGC生存信号和莫里森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。我们的长期目标是确定新的药理学策略，以保护文化和临床前动物模型中的视神经，并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Ootic神经病。