Mechanisms of Optic Nerve Stroke Neuroprotection

视神经中风的神经保护机制

基本信息

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
项目类别：
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

项目摘要

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）：非动脉前缺血性视神经病（NAION）是视神经（ON）梗塞，是突然的视神经（ON）相关视力丧失的最常见原因，NAION每年影响约15,000个个体，并且没有有效的治疗。关于NAION病理生理学的机制知之甚少。我们的实验室开发了第一个啮齿动物和灵长类动物的幼稚模型，这些模型几乎已经验证了NAION中发现的所有发现，并且我们严重剖析了NAIONS可能的过程。我们已经确定，早期和晚期炎症性变化在NAION模型开发和损害中起着关键作用。 NAION模型诱导后不久，头部水肿和隔室综合征以及可溶性炎症细胞因子表达和进行性缺血。后来（> 3D）的变化包括明显的细胞炎症浸润，M1增加（退化性巨噬细胞反应）和M2降低（再生巨噬细胞反应）活性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）确定为可能治疗早期疾病的第一种药物。在AIM 1中，我们将分别评估PGJ2的神经保护机制，确认其个人身份和最大效应。然后，我们将确定这些机制是否协同起作用，以最大化神经保护作用。在AIM 2中，我们将确定选择性免疫调节神经保护M2巨噬细胞炎症反应是否会减少RGC和髓磷脂功能障碍和细胞死亡，并改善感染后恢复。这些干预措施的结果将使用多种技术评估，以在组织化学和功能上在基因表达水平上进行量化。这种结合的早期和以后的方法旨在最大程度地提高临床有效治疗的NAION和相关疾病，并大大改善了NAION恢复。