Mechanisms of Optic Nerve Stroke Neuroprotection

视神经中风的神经保护机制

• 批准号: 8901174
• 负责人: STEVEN L BERNSTEIN
• 金额: $ 37.61万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8901174
• 关键词: Acute; Affect; Age-Years; Agonist; Anterior Ischemic Optic Neuropathy; Axon; Biological; Blindness; Cell Survival; Cell surface; Cells; Cellular Infiltration; Cessation of life; Clinical; Clinical Trials; Compartment syndromes; Development; Disease; Down-Regulation; Edema; Electrophysiology (science); Equilibrium; Event; Functional disorder; Funding; Gene Expression; Health; Hour; Immunomodulators; Individual; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intervention; Invaded; Ischemia; Ischemic Optic Neuropathy; Laboratories; Lead; Modeling; Molecular; Mus; Myelin; NF-kappa B; Natural regeneration; Oligodendroglia; Optic Disk; Optic Nerve; Outcome; PPAR gamma; Pathway interactions; Patients; Physicians; Play; Primates; Process; Prostaglandins; Proteins; Recovery; Research Design; Retinal Ganglion Cells; Rodent; Rodent Model; Spinal cord injury; Staging; Stroke; Techniques; Testing; Time; Transgenic Model; Translating; Up-Regulation; Visual; axon injury; clinically relevant; cytokine; design; effective therapy; experience; falls; immunoregulation; improved; in vivo; ischemic lesion; macrophage; model development; neuroprotection; novel strategies; receptor; repaired; response

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：非动脉性前缺血性视神经病变（NAION）是一种视神经（ON）梗死，是突发性视神经（ON）相关视力丧失的最常见原因，NAION每年影响约15,000人，没有有效的治疗方法。目前对NAION的病理生理机制知之甚少。我们的实验室开发了第一个啮齿动物和灵长类动物的NAION模型，这些模型已经验证了在NAION中发现的几乎所有发现，并且我们可以批判性地解剖NAION的可能过程。我们已经确定，早期和晚期炎症变化在NAION模型的发展和损伤中起关键作用。NAION模型诱导后不久，随着可溶性炎性细胞因子的表达和进行性缺血，出现ON头部水肿和筋膜室综合征。后期（>3d）变化包括明显的细胞炎症浸润，M1（退行性巨噬细胞反应）增加，M2（再生性巨噬细胞反应）活性降低，轴突和少突胶质细胞损伤进行性。这些反应最终导致视网膜神经节细胞（RGC）和少突胶质细胞死亡。我们发现前列腺素J2 （PGJ2）是第一种可能治疗早期疾病的药物。在aim 1中，我们将分别评估PGJ2的神经保护机制，确认它们的个体身份和最大作用。然后我们将确定这些机制是否协同作用，以最大限度地保护神经。在目的2中，我们将确定选择性免疫调节神经保护性M2巨噬细胞炎症反应是否会减少RGC和髓鞘功能障碍和细胞死亡，并改善梗死后恢复。这些干预的结果将使用各种技术进行评估，以量化基因表达水平，组织化学和功能上的影响。这种早期和晚期结合的方法旨在最大限度地开发临床上有效的治疗NAION和相关疾病的方法，并大大提高NAION后的恢复。