Mechanisms of optic nerve stroke neuroprotection

描述（由申请人提供）：非动脉性缺血性视神经病变（NAION）是一种视神经中风，是导致突发性视神经（ON）相关视力丧失的最常见原因，每年影响5700名美国人。我开发了第一个啮齿动物中风模型（啮齿动物前缺血性视神经病变；rAION），在许多方面与临床的NAION非常相似。像NAION一样，rAION也会产生ON水肿，并通过破坏视网膜神经节细胞的轴突和组成ON的细胞来杀死视网膜神经节细胞（rgc）。我可以第一次精确地描述非缺血性损伤的进展，确定早期缺血的关键成分，并量化治疗效果。约25%的NAION患者自发部分恢复，表明有效的NAION治疗是可能的。我的实验室已经确定了可能形成临床治疗基础的特定途径。我的初步数据显示前列腺素J2 (PGJ2)，前列腺素D2 （PGD2）的活性代谢物，减少脑卒中后ON水肿，提高RGC生存率。该建议采用双管齐下的方法来保护RGCs并增强视神经梗死后的视神经恢复。首先，通过阻断导致ON水肿的早期病理事件。其次，通过在梗死后期招募外源性巨噬细胞来改善ON修复和再生。两个具体目标是：1。通过使用PGJ2阻断诱导型一氧化氮（iNOS）的产生和活性，抑制on后早期梗死水肿。我会利用rAION模型，结合定量细胞分析和分子技术。我将利用我的实验室开创的一种新的血管分析技术，评估PGJ2对中风后血管功能的影响。我将用失活的iNOS基因敲除小鼠来证实PGJ2抑制iNOS的表达。我预测inos灭活小鼠将减少梗死后ON水肿，但对额外的PGJ2-PGD2调节没有反应。2. 选择性地增加中风后炎症，以改善视网膜和ON的恢复。这将通过将细胞因子粒细胞-巨噬细胞集落刺激因子传递到脑卒中后的ON，刺激ON系统巨噬细胞募集来实现。我预测这种治疗将增加梗死后的RGC存活，并通过去除退化的髓鞘，减少疤痕，并改善on -轴突再生。公共卫生相关性：非动脉性视神经（ON）中风（NAION）目前每年影响超过5700名美国人，并且没有有效的治疗方法。我已经开发了第一个相关的NAION模型，并确定了非中风相关的途径，这可能成为有效治疗这种无法治疗的疾病的基础。我的建议采用了双管齐下的转化方法：减少中风后视神经肿胀，激活内在炎症机制来保护神经元，去除退化物质，并刺激再生。

DESCRIPTION (provided by applicant): Non-arteritic ischemic optic neuropathy (NAION), an optic nerve stroke, is the most common cause of sudden optic nerve (ON)-related vision loss, affecting 5700 Americans every year. I have developed the first rodent stroke model (rodent anterior ischemic optic neuropathy; rAION), closely resembling clinical NAION in many respects. Like NAION, rAION produces ON edema, and kills retinal ganglion cells (RGCs), by destroying their axons and cells comprising the ON. I can, for the first time, precisely characterize the progression of ON-ischemic damage, identify key components of early ischemia and quantify treatment effectiveness. Spontaneous partial recovery occurs in ~25% of NAION-affected individuals, suggesting that effective NAION treatment is possible. My lab has identified specific pathways that may form the basis for clinical treatment. My preliminary data reveals that prostaglandin J2 (PGJ2), the active metabolite of prostaglandin D2 (PGD2), reduces post-stroke ON edema and improves RGC survival. This proposal utilizes a two pronged approach to protect RGCs and enhance optic nerve recovery after optic nerve infarct. First, by blocking early pathological events contributing to ON edema. Second, by recruiting extrinsic macrophages later in the course of the infarct to improve ON repair and regeneration. The two specific aims are: 1. Inhibit early post-ON infarct edema by using PGJ2 to block inducible nitric oxide (iNOS) production and activity. I will utilize the rAION model, coupled to quantitative cell analysis, and molecular techniques. I will evaluate PGJ2`s effects on post-stroke ON vascular function, utilizing a new vascular analytical technique my lab has pioneered. I will confirm that PGJ2 inhibits iNOS expression using a knockout mouse with an inactivated iNOS gene. I predict that iNOS-inactivated mice will have reduced post-infarct ON edema, but will not respond to additional PGJ2-PGD2 modulation. 2. Selectively increase later post-stroke inflammation to improve retinal and ON recovery. This will be accomplished by delivering the cytokine granulocyte-macrophage colony stimulating factor to the post-stroke ON, stimulating ON-systemic macrophage recruitment. I predict that this treatment will increase post-infarct RGC survival, and by removing degenerating myelin, reduce scarring, and improve ON-axonal regeneration. PUBLIC HEALTH RELEVANCE: Nonarteritic optic nerve (ON) stroke (NAION) currently affects over 5700 Americans each year, and there are no effective treatments. I have developed the first relevant model of NAION, and identified ON-stroke related pathways that may form the basis for effective treatment for this otherwise untreatable disorder. My proposal utilizes a two pronged translational approach: reduce post-stroke swelling compromising the optic nerve, and activating intrinsic inflammatory mechanisms to preserve neurons, remove degenerating material, and stimulate regeneration.