Triazine-based compounds to promote regeneration in optic neuropathies
基于三嗪的化合物促进视神经病变的再生
基本信息
- 批准号:8284307
- 负责人:
- 金额:$ 3.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-01 至 2013-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAnimal ModelAnterior Ischemic Optic NeuropathyAxonBiological AssayBlindnessBrainCell DeathCessation of lifeChemicalsCicatrixClinicDevelopmentDiseaseDrug KineticsFunctional disorderGoalsIn VitroInjuryInterventionLeadLibrariesModelingMyelinNatural regenerationNeuraxisNeuronsNeuropathyOptic NerveOptic Nerve InjuriesPatientsPharmaceutical PreparationsRelative (related person)RetinalRetinal Ganglion CellsSpinal cord injuryTestingTranslationsTriazinesVisionbasecentral nervous system injurychemical propertydesigneffective therapygrowth inhibitory proteinsimprovedin vivoinjuredneurite growthnovelnovel strategiesnovel therapeuticsoptic nerve disorderoptic nerve regeneration
项目摘要
DESCRIPTION (provided by applicant): Non-arteritic anterior ischemic optic neuropathy (NAION) is the most common cause of optic nerve-related acute loss of vision in the US; there is no effective treatment. NAION causes injury to optic nerve axons, leading to dysfunction and death of retinal ganglion cells (RGCs). Interventions to enhance RGC regeneration could be applied before RGC death, to reverse dysfunction by allowing RGCs to reconnect with their targets in the brain. Enhancement of optic nerve regeneration is a major goal for patients with NAION and other neuropathies. The lack of regeneration-promoting therapies in NAION and other diseases reflects barriers to regeneration in the injured central nervous system (CNS), including growth-inhibitory proteins associated with myelin and the glial scar. Strategies to promote regeneration by overcoming these barriers have shown efficacy in animal models, but novel strategies and translation to the clinic are needed. We have performed a phenotypic screen using a library of novel drug-like triazine compounds on primary mammalian neurons, and have identified 4 compounds capable of increasing neurite growth on a substrate of inhibitory CNS myelin. These compounds a) act on different neuronal types, including RGCs, b) are potent, c) overcome inhibition in several assays relevant to CNS injury, and d) may act by novel mechanisms. We have now shown that one compound, AA4F05, promotes regeneration in an animal model of retinal injury, as well as in a model of spinal cord injury. AA4F05 and its relatives are exciting candidates to lead to novel drugs for promoting regeneration of RGCs and other CNS neurons. Although AA4F05 has favorable chemical properties and is active both in vitro and in vivo, there has been no attempt to optimize its activity or pharmacokinetics. The present proposal will use AA4F05 as a starting point for the development of new compounds with the potential to substantially improve regeneration of damaged axons from RGCs. Derivatives will be tested in primary neurons in vitro (primary and secondary screens), and the best candidates will be tested in 2 models of optic nerve injury.
描述(由申请人提供):非动脉炎性前部缺血性视神经病变(NAION)是美国视神经相关急性视力丧失的最常见原因;目前尚无有效治疗方法。NAION引起视神经轴突损伤,导致视网膜神经节细胞(RGC)功能障碍和死亡。可以在RGC死亡之前进行干预以增强RGC再生,通过允许RGC与其在大脑中的靶点重新连接来逆转功能障碍。增强视神经再生是NAION和其他神经病变患者的主要目标。 NAION和其他疾病中缺乏再生促进疗法反映了受损中枢神经系统(CNS)再生的障碍,包括与髓鞘和胶质瘢痕相关的生长抑制蛋白。通过克服这些障碍来促进再生的策略已经在动物模型中显示出有效性,但需要新的策略和临床翻译。我们已经进行了一个表型筛选,使用一个新的药物样三嗪化合物的图书馆对原代哺乳动物神经元,并已确定4种化合物能够增加神经突起生长的抑制性中枢神经系统髓鞘的基板上。这些化合物a)作用于不同的神经元类型,包括RGC,B)是有效的,c)在与CNS损伤相关的几种测定中克服抑制,和d)可以通过新的机制起作用。我们现在已经证明,一种化合物AA 4F 05在视网膜损伤的动物模型以及脊髓损伤的模型中促进再生。AA 4F 05和它的亲属是令人兴奋的候选人,导致新的药物,促进再生的RGCs和其他中枢神经系统神经元。虽然AA 4F 05具有良好的化学性质,并且在体外和体内都具有活性,但尚未尝试优化其活性或药代动力学。本提案将使用AA 4F 05作为开发新化合物的起点,这些新化合物具有显著改善RGC受损轴突再生的潜力。衍生物将在体外原代神经元中进行测试(初级和二级筛选),最佳候选物将在2种视神经损伤模型中进行测试。
项目成果
期刊论文数量(1)
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 novel rodent model of posterior ischemic optic neuropathy.
- DOI:10.1001/2013.jamaophthalmol.271
- 发表时间:2013-02
- 期刊:
- 影响因子:8.1
- 作者:Wang Y;Brown DP Jr;Duan Y;Kong W;Watson BD;Goldberg JL
- 通讯作者:Goldberg JL
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John L Bixby其他文献
John L Bixby的其他文献
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{{ truncateString('John L Bixby', 18)}}的其他基金
Targeting Multiple Kinases to Treat Experimental Spinal Cord Injury.
靶向多种激酶治疗实验性脊髓损伤。
- 批准号:
10393353 - 财政年份:2017
- 资助金额:
$ 3.28万 - 项目类别:
Targeting Multiple Kinases to Treat Experimental Spinal Cord Injury
靶向多种激酶治疗实验性脊髓损伤
- 批准号:
9917854 - 财政年份:2017
- 资助金额:
$ 3.28万 - 项目类别:
Targeting Multiple Kinases to Treat Experimental Spinal Cord Injury
靶向多种激酶治疗实验性脊髓损伤
- 批准号:
10160972 - 财政年份:2017
- 资助金额:
$ 3.28万 - 项目类别:
Regenbase: A Searchable Database to Organize Regeneration Knowledge via Ontologie
Regenbase:通过 Ontologie 组织再生知识的可搜索数据库
- 批准号:
8465934 - 财政年份:2012
- 资助金额:
$ 3.28万 - 项目类别:
Regenbase: A Searchable Database to Organize Regeneration Knowledge via Ontologie
Regenbase:通过 Ontologie 组织再生知识的可搜索数据库
- 批准号:
8653627 - 财政年份:2012
- 资助金额:
$ 3.28万 - 项目类别:
Regenbase: A Searchable Database to Organize Regeneration Knowledge via Ontologie
Regenbase:通过 Ontologie 组织再生知识的可搜索数据库
- 批准号:
8365739 - 财政年份:2012
- 资助金额:
$ 3.28万 - 项目类别:
Regenbase: A Searchable Database to Organize Regeneration Knowledge via Ontologie
Regenbase:通过 Ontologie 组织再生知识的可搜索数据库
- 批准号:
8839677 - 财政年份:2012
- 资助金额:
$ 3.28万 - 项目类别:
Triazine-based compounds to promote regeneration in optic neuropathies
基于三嗪的化合物促进视神经病变的再生
- 批准号:
8128170 - 财政年份:2011
- 资助金额:
$ 3.28万 - 项目类别:
Novel Compounds That Overcome Glial Inhibition of Axonal Regeneration
克服神经胶质细胞对轴突再生的抑制的新型化合物
- 批准号:
8394926 - 财政年份:2009
- 资助金额:
$ 3.28万 - 项目类别:
Novel Compounds That Overcome Glial Inhibition of Axonal Regeneration
克服神经胶质细胞对轴突再生的抑制的新型化合物
- 批准号:
7582047 - 财政年份:2009
- 资助金额:
$ 3.28万 - 项目类别:
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