Mechanisms of optic nerve stroke neuroprotection

描述(申请人提供)：非动脉炎缺血性视神经病变(NAION)是一种视神经中风，是与视神经(ON)相关的突发性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在水肿时产生，并通过破坏视网膜神经节细胞(RGC)的轴突和组成ON的细胞来杀死RGC。我可以第一次准确地描述缺血损伤的进展，识别早期缺血的关键成分，并量化治疗效果。在受NAION影响的患者中，约有25%的人出现了自发的部分恢复，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。我的初步数据显示，前列腺素D2(PGD2)的活性代谢物前列腺素J2(PGJ2)可以减轻中风后的浮肿，并提高RGC的存活率。这项建议利用双管齐下的方法来保护视网膜节细胞和促进视神经梗死后的视神经恢复。首先，通过阻断早期的病理事件导致水肿症。第二，在脑梗塞后的过程中招募外源性巨噬细胞，以改善修复和再生。两个特定的目的是：1.用PGJ2阻断诱导型一氧化氮合酶(INOS)的产生和活性，从而抑制早期脑梗塞后的水肿。我将利用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首创的一项新的血管分析技术，评估前列腺素2对中风后血管功能的影响。我将用一只带有失活iNOS基因的敲除小鼠来证实PGJ2抑制iNOS的表达。我预测iNOS失活的小鼠将减少脑梗塞后的水肿，但不会对额外的PGJ2-PGD2调节产生反应。2.选择性地增加卒中后炎症，以改善视网膜和促进恢复。这将通过将细胞因子粒细胞-巨噬细胞集落刺激因子输送到中风后，刺激全身巨噬细胞募集来实现。我预测，这种治疗方法将增加梗塞后RGC的存活率，并通过去除退化的髓鞘，减少瘢痕形成，促进轴突再生。公共卫生相关性：非动脉炎性视神经中风(NAION)目前每年影响超过5700名美国人，目前还没有有效的治疗方法。我已经开发了第一个相关的NAION模型，并确定了与中风相关的通路，这些通路可能构成这种无法治疗的疾病的有效治疗的基础。我的建议采用了一种双管齐下的翻译方法：减少中风后损害视神经的肿胀，以及激活内在炎症机制以保护神经元，移除退化物质，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.