Mechanisms of Optic Nerve Stroke Neuroprotection

视神经中风的神经保护机制

• 批准号: 8762089
• 负责人: STEVEN L BERNSTEIN
• 金额: $ 38.38万
• 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/8762089
• 关键词: 9-deoxy-delta-9-prostaglandin D2; 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; Pathway interactions; Patients; Physicians; Play; Primates; Process; Proteins; Recovery; Research Design; Retinal Ganglion Cells; Rodent; Rodent Model; Spinal cord injury; Staging; Stroke; Techniques; Testing; Time; Transgenic Model; Translating; Up-Regulation; Visual; 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）：非动脉炎性前部缺血性视神经病变（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例患者，目前尚无有效治疗方法。关于NAION的病理生理学机制知之甚少。我们的实验室开发了第一个啮齿动物和灵长类动物NAION模型，这些模型已经被验证用于NAION中发现的几乎每一个发现，我们批判性地剖析了NAION可能的过程。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。在NAION模型诱导后不久，ON头部水肿和室间隔综合征伴随可溶性炎性细胞因子表达和进行性缺血发生沿着。后期（>3d）变化包括显著的细胞炎症浸润，M1（退行性巨噬细胞反应）活性增加，M2（再生巨噬细胞反应）活性降低，以及进行性轴突和少突胶质细胞损伤。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。我们将前列腺素J2（PGJ2）确定为第一种可能治疗早期疾病的药物。在目标1中，我们将单独评估PGJ 2的神经保护机制，确认它们的个体身份和最大效果。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。在目标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。这些干预措施的结果将使用各种技术进行评估，以量化基因表达水平，组织化学和功能的影响。这种早期和晚期方法的组合旨在最大限度地开发NAION和相关疾病的临床有效治疗方法，并大大改善NAION后的恢复。