Development of redox-active therapies for ischemic optic neuropathy

缺血性视神经病氧化还原活性疗法的开发

基本信息

批准号：
8975773
负责人：
Leonard A Levin
金额：
$ 22.95万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2017-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Anterior ischemic optic neuropathy (AION) is the most common cause of acute optic nerve disease in men and women aged 50 years or more. It causes painless visual loss, loss of part of the visual field, and swelling of the optic nerve insie the eye. Unfortunately not only does vision rarely recover, but there is no successful treatment, despite 2 medium-sized randomized clinical trials and several small-scale studies. As part of a program to find new ways of treated optic neuropathy, we developed novel drugs that chemically reduce disulfide bonds and protect retinal ganglion cell axons, the fibers that project through the optic nerve from the eye to the brain. These "phosphine- borane complexes" are effective in rat optic nerve transection and experimental glaucoma. They presumably reduce intra- or intermolecular disulfide bonds in one or more critical target proteins. However, we do not know the identity of the proteins undergoing oxidative disulfide formation in diseases such as AION. If those targets can be identified, they can serve as the basis for making more specific phosphine-borane complexes, which then could be used as novel AION therapeutics. We propose to use a sensitive redox proteomic screen to identify the protein target(s) within the optic nerve that undergo sulfhydryl oxidation after rodent AION, and then use the putative target(s) to synthesize a library of 20-30 potentially more specific phosphine- borane complexes. We then will determine a lead candidate by finding which optimally reduces the critical targets, and test it in the rAION model. This lead phosphine-borane complex could then be a candidate for translation into primate models and eventually clinical trial planning.

描述（由申请人提供）：前缺血性视神经神经病（AION）是50岁以上男性和女性急性视神经疾病的最常见原因。它会导致无痛的视觉丧失，视野的一部分丧失以及视神经的肿胀。不幸的是，尽管有2项中型随机临床试验和几项小规模研究，但视力不仅很少恢复，而且没有成功的治疗方法。作为找到治疗的视觉神经病的新方法的一部分，我们开发了新的药物，可以化学减少二硫键键并保护视网膜神经节细胞轴突，视网膜神经节细胞轴突，这是通过视神经从眼睛到大脑的纤维进行的纤维。这些“磷酸 - 硼烷复合物”在大鼠视神经横向和实验青光眼中有效。它们大概减少了一种或多种关键靶蛋白中的分子内或分子间二硫键。但是，我们不知道在诸如AION之类的疾病中经历氧化二硫化物形成的蛋白质的身份。如果可以确定这些靶标，它们可以作为制造更特定的磷酸 - 硼烷复合物的基础，然后可以用作新型的Aion治疗剂。我们建议使用敏感的氧化还原蛋白质组学筛选来识别啮齿动物Aion后经历硫酰基氧化的视神经内的蛋白质靶标，然后使用假定的靶标（S）合成20-30个库的库，潜在的可能更特异性的磷酸磷酸磷酸乙烷复合物。然后，我们将通过查找最佳减少关键目标并在Raion模型中进行测试来确定铅候选者。然后，这种铅磷酸 - 硼烷复合物可以成为转化为灵长类动物模型并最终临床试验计划的候选者。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A quantitative approach to the spread of variance in translational research using Monte Carlo simulation.

DOI：
10.1038/s41598-022-09921-3
发表时间：
2022-04-15
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Cukurova, Feyza;Gustavson, Britta P.;Griborio-Guzman, Andres G.;Levin, Leonard A.
通讯作者：
Levin, Leonard A.

Axonal degeneration induces distinct patterns of phosphatidylserine and phosphatidylethanolamine externalization.