Preclinical analysis of ischemic optic nerve treatment
缺血性视神经治疗的临床前分析
基本信息
- 批准号:8138465
- 负责人:
- 金额:$ 47.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-01 至 2014-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAmericanAnimal ModelAnimalsAnterior Ischemic Optic NeuropathyBiological ModelsBiological PreservationBlindnessBlood VesselsCell SurvivalClinicalClinical TreatmentClinical effectivenessDataDisease modelDrug usageEarly treatmentEdemaFailureFunctional disorderGene ExpressionGrantHealthHemorrhageHistologicHumanInfarctionInstitutional Review BoardsIschemiaIschemic Optic NeuropathyLesionMagnetic Resonance ImagingMetabolic PathwayModelingNeuroprotective AgentsOptic DiskOptic NerveOptical Coherence TomographyPathway interactionsPatientsPharmaceutical PreparationsPrimatesProbabilityProstaglandin D2RecoveryReducing AgentsReportingResolutionRetinalRetinal Ganglion CellsRodentRodent ModelSeveritiesSpeedStrokeSwellingTechniquesTestingTimeTissuesTranslatingTranslationsVascular Endothelial Growth Factorseffective therapyimprovedin vivonervous system disorderneuron lossnonhuman primatepost strokepre-clinicalresponsesuccesstranslational studytreatment trial
项目摘要
DESCRIPTION (provided by applicant): Nonarteritic anterior ischemic optic neuropathy (NAION) is an optic nerve (ON) stroke and the most common cause of sudden optic nerve-related vision loss. NAION affects more than 6000 Americans every year, often bilaterally, with no currently effective treatments. Every NAION clinical treatment trial has failed. A major reason for these failures is the lack of appropriate animal models closely resembling NAION physiologically and pathologically, and that would allow testing of relevant treatments for translation to the human condition.I have now generated an old-world primate model of non-arteritic anterior ischemic optic neuropathy (pNAION). My preliminary data reveal a high degree of similarity between pNAION and human NAION. A great advantage of the current proposal is my ability to test potential optic nerve stroke treatments, using well- defined model systems, from rodents through old-world primates. This will yield improved potential for clinical success. I have assembled an incredibly capable, highly focused, integrated and dedicated team for the proposal. My preliminary data reveal that activating the Nonarteritic anterior ischemic optic neuropathy (NAION) (PGD2) metabolic pathway after rodent ON infarct reduces ON edema and improves long-term retinal ganglion cell (RGC) survival. This pathway is highly conserved from rodents to humans. Recent anecdotal studies also report improved clinical function in NAION patients following treatment with other agents that reduce tissue edema. I hypothesize that, by reducing early ON edema in pNAION, I can improve post-infarct RGC survival and optic nerve function. This translational study will determine whether PGD2 activation and ON edema reduction are likely to be effective neuroprotective treatments in NAION. There are three subaims: a. Characterize early changes in retinal and optic nerve function with ultimate neuronal loss, and tissue remodeling, to determine the appropriate intervals for early intervention and maximum recovery. b. Determine if early edema reduction improves post-stroke optic nerve function. I will activate the PGD2 pathway to reduce pNAION-induced ON edema and evaluate ON function using high-resolution optical coherence tomography (OCT), electrophysiological techniques, and magnetic resonance (MR) imaging. In vivo results will be correlated with histopathologic and immunochemical findings. c. Compare PGD2 activation with currently available VEGF-blocking drugs used to reduce clinical NAION- induced ON edema, to confirm the potential clinical effectiveness of the edema-reduction approach. PUBLIC HEALTH RELEVANCE: Nonarteritic optic nerve (ON) stroke (NAION) currently affects over 6000 Americans each year. There are no effective treatments, partly because no model of the disease in a closely-related species was available for evaluating approaches that can be translated into clinical therapy. I have developed the first relevant non-human primate model of NAION, and have identified a conserved pathway effective in treating rodent ON stroke. This proposal will determine whether by activating this pathway, and additionally by reducing post-stroke ON swelling using a commercially available drug, we can improve post-ON stroke function and speed recovery after infarct.
描述(由申请人提供):非动脉前缺血性视神经病(NAION)是视神经(ON)中风,也是突然的视神经相关视力丧失的最常见原因。 NAION每年通常会双侧影响6000多名美国人,目前没有有效的治疗方法。每项NAION临床治疗试验都失败了。这些失败的主要原因是缺乏适当的动物模型在生理和病理上与NAION紧密相似,这将允许对相关治疗方法进行转化为人类状况。我现在已经产生了一种旧世界的灵长类动物模型的旧缺血性缺血性神经性神经病变(PNAion)。我的初步数据揭示了PNAion和人类幼体之间的相似性。当前建议的一个很大的优势是,我能够使用定义良好的模型系统从啮齿动物到旧世界灵长类动物测试潜在的视神经中风处理。这将带来临床成功的潜力提高。我召集了一个能力令人难以置信的能力,高度集中,集成和专门的团队,以供该提案。我的初步数据表明,在啮齿动物梗塞后,激活非动脉前缺血性缺血性视神经病神经病(NAION)(NAION)(PGD2)代谢途径减少了水肿,并改善了长期视网膜神经节细胞(RGC)的存活率。从啮齿动物到人类,这条途径是高度保守的。最近的轶事研究还报告说,与其他减少组织水肿的药物治疗后,NAION患者的临床功能提高了。我假设,通过在PNAion的水肿早期减少,我可以改善侵略后RGC存活和视神经功能。这项翻译研究将确定PGD2激活和减少水肿是否可能是NAIN中有效的神经保护治疗。有三个子:表征具有最终神经元损失和组织重塑的视网膜和视神经功能的早期变化,以确定适当的时间间隔,以进行早期干预和最大恢复。 b。确定早期水肿是否减少是否改善了势后视神经功能。我将激活PGD2途径,以减少水肿诱导的PNAion途径,并使用高分辨率光相干断层扫描(OCT),电生理技术和磁共振(MR)成像对功能进行评估。体内结果将与组织病理学和免疫化学的发现相关。 c。将PGD2激活与目前可用的VEGF阻断药物进行比较,用于减少水肿诱导的临床NAION,以确认水肿还原方法的潜在临床有效性。公共卫生相关性:目前每年有6000多名美国人的中风(NAION)非动态性视神经(ON)。没有有效的治疗方法,部分是因为在密切相关的物种中没有该疾病模型可用于评估可以转化为临床治疗的方法。我已经开发了第一个相关的非人类灵长类动物模型,并确定了有效治疗中风啮齿动物的保守途径。该提案将通过激活该途径来确定是否通过使用市售药物减少溶胀后的势后,我们可以改善梗塞后的中风功能和速度恢复。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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STEVEN L BERNSTEIN其他文献
STEVEN L BERNSTEIN的其他文献
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{{ truncateString('STEVEN L BERNSTEIN', 18)}}的其他基金
The role of optic nerve lamina region stem cells in age-related optic nerve disease
视神经板区域干细胞在年龄相关性视神经疾病中的作用
- 批准号:
10443202 - 财政年份:2022
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$ 47.31万 - 项目类别:
The role of optic nerve lamina region stem cells in age-related optic nerve disease
视神经板区域干细胞在年龄相关性视神经疾病中的作用
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10707014 - 财政年份:2022
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Preclinical Analysis of Ischemic Optic Nerve Treatment
缺血性视神经治疗的临床前分析
- 批准号:
9367979 - 财政年份:2017
- 资助金额:
$ 47.31万 - 项目类别:
Preclinical analysis of ischemic optic nerve treatment
缺血性视神经治疗的临床前分析
- 批准号:
8531941 - 财政年份:2009
- 资助金额:
$ 47.31万 - 项目类别:
Preclinical analysis of ischemic optic nerve treatment
缺血性视神经治疗的临床前分析
- 批准号:
7908779 - 财政年份:2009
- 资助金额:
$ 47.31万 - 项目类别:
Preclinical analysis of ischemic optic nerve treatment
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Preclinical analysis of ischemic optic nerve treatment
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