Nonarteritic anterior ischemic optic neuropathy (NAION) is an optic nerve (ON) infarct, and the most common cause of sudden optic nerve (ON) related vision loss, NAION affects ~15,000 individuals/year and has no effective treatments. Little is known about the mechanisms in NAION pathophysiology. Our lab developed the first rodent and primate NAION models that have been validated for nearly every finding found in NAION, and us to critically dissect NAIONs likely processes. We have determined that early and late inflammatory changes play a key role in NAION model development and damage. Soon after NAION model induction, ON head edema and a compartment syndrome occur along with soluble inflammatory cytokine expression and progressive ischemia. Later (>3d) changes include significant cellular inflammatory infiltration, with increased M1 (degenerative macrophage response) and decreased M2 (regenerative macrophage response) activities, and progressive axon- and oligodendrocyte damage. These responses ultimately result in retinal ganglion cell (RGC) and oligodendrocyte death. We identified prostaglandin J2 (PGJ2) as the first agent that can potentially treat early stage disease.
In aim 1, we will separately evaluate PGJ2's neuroprotective mechanisms, confirming their individual identities and their maximal effects. We will then determine whether these mechanisms act synergistically, to maximize neuroprotection.
In aim 2, we will determine whether selectively immunomodulating the neuroprotective M2 macrophage inflammatory response will reduce RGC and myelin dysfunction and cellular death, and improve post-infarct recovery. Results of these interventions will be evaluated using a variety of techniques, to quantify effects at the gene expression level, histochemically and functionally. This combination early and later approaches is designed to maximize development of clinically effective treatments for NAION and related diseases, and greatly improve post- NAION recovery.
Nonarteritic anterior ischemic optic neuropathy (NAION), the most common cause of sudden optic nerve related vision loss, affects 15,000 individuals/year and has no effective treatments. We have identified the first agent (PGJ2) that can potentially treat this disease. We will maximize PGJ2's mechanisms to improve early neuroprotection. NAION and its models also show alterations in invading inflammatory cells that result in later additional damage. By modifying the later inflammatory component, we will improve recovery and repair. Results from this study will directly translate into early and later effective treatmens for this disease.
|Mehrabian, Zara; Guo, Yan; Weinreich, Daniel et al. (2017) Oligodendrocyte death, neuroinflammation, and the effects of minocycline in a rodent model of nonarteritic anterior ischemic optic neuropathy (rNAION). Mol Vis 23:963-976|
|Guo, Yan; Mehrabian, Zara; Bernstein, Steven L (2016) The Rodent Model of Nonarteritic Anterior Ischemic Optic Neuropathy (rNAION). J Vis Exp :|
|Nicholson, James D; Guo, Yan; Bernstein, Steven L (2016) SUR1-Associated Mechanisms Are Not Involved in Ischemic Optic Neuropathy 1 Day Post-Injury. PLoS One 11:e0148855|
|Guo, Yan; Johnson, Mary A; Mehrabian, Zara et al. (2016) Dendrimers Target the Ischemic Lesion in Rodent and Primate Models of Nonarteritic Anterior Ischemic Optic Neuropathy. PLoS One 11:e0154437|
|Bernstein, Steven L; Miller, Neil R (2015) Ischemic optic neuropathies and their models: disease comparisons, model strengths and weaknesses. Jpn J Ophthalmol 59:135-47|
|Mathews, Michaela K; Guo, Yan; Langenberg, Patricia et al. (2015) Ciliary neurotrophic factor (CNTF)-mediated ganglion cell survival in a rodent model of non-arteritic anterior ischaemic optic neuropathy (NAION). Br J Ophthalmol 99:133-7|
|Ziesel, Alison; Bernstein, Steven; Wong, Paul W (2014) Generation of a foveomacular transcriptome. Mol Vis 20:947-54|
|Slater, Bernard J; Vilson, Fernandino L; Guo, Yan et al. (2013) Optic nerve inflammation and demyelination in a rodent model of nonarteritic anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci 54:7952-61|
|Touitou, Valerie; Johnson, Mary A; Guo, Yan et al. (2013) Sustained neuroprotection from a single intravitreal injection of PGJ2 in a rodent model of anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci 54:7402-9|
|Nicholson, James D; Puche, Adam C; Guo, Yan et al. (2012) PGJ(2) provides prolonged CNS stroke protection by reducing white matter edema. PLoS One 7:e50021|
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