Mechanisms of optic nerve stroke neuroprotection

描述（由申请人提供）：非动脉炎性缺血性视神经病变（NAION）是一种视神经卒中，是突发性视神经（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（啮齿动物前部缺血性视神经病变; rAION），在许多方面与临床NAION非常相似。像NAION一样，rAION产生ON水肿，并通过破坏它们的轴突和构成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表征ON缺血性损伤的进展，识别早期缺血的关键成分并量化治疗效果。自发部分恢复发生在~25%的NAION受影响的个体中，这表明有效的NAION治疗是可能的。我的实验室已经确定了可能构成临床治疗基础的特定途径。我的初步数据表明，前列腺素J2（PGJ 2），前列腺素D2（PGD 2）的活性代谢产物，减少中风后ON水肿，提高RGC生存。该建议采用双管齐下的方法来保护RGC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。第二，通过在梗塞过程后期募集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PGJ 2阻断诱导型一氧化氮（iNOS）的产生和活性来抑制ON后早期梗死水肿。我将利用rAION模型，结合定量细胞分析和分子技术。我将评估PGJ 2对中风后血管功能的影响，利用我的实验室开创的一种新的血管分析技术。我将使用具有失活的iNOS基因的敲除小鼠证实PGJ 2抑制iNOS表达。我预测iNOS失活的小鼠将具有减少的梗死后ON水肿，但将不响应于额外的PGJ 2-PGD 2调节。2.选择性增加中风后炎症，以改善视网膜和ON恢复。这将通过向中风后ON递送细胞因子粒细胞-巨噬细胞集落刺激因子，刺激ON-全身巨噬细胞募集来实现。我预测，这种治疗将增加梗死后RGC的存活率，并通过清除变性髓鞘，减少瘢痕形成，并改善ON-轴突再生。公共卫生相关性：非动脉炎性视神经（ON）卒中（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NAION的第一个相关模型，并确定了可能形成有效治疗这种无法治疗的疾病的基础的ON-卒中相关通路。我的建议采用了双管齐下的翻译方法：减少中风后肿胀损害视神经，并激活内在的炎症机制，以保护神经元，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.