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.
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.
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