Opioidergic System: Its Role(s) in Glaucoma

阿片类药物系统：其在青光眼中的作用

• 批准号: 8126325
• 负责人: Shahid Husain
• 金额: $ 35.4万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8126325
• 关键词: Acute; Agonist; Animal Model; Apoptotic; Astrocytes; Atrophic; BMP8 Gene; Benchmarking; Biomechanics; Blindness; Chronic; Complex; Data; Development; Dynorphins; Endorphins; Enkephalins; Enzyme-Linked Immunosorbent Assay; Enzymes; Etiology; Event; Extracellular Matrix; Eye; Gelatinase A; Glaucoma; Goals; Human; Hypoxia; Immune; Immunohistochemistry; Individual; Inflammatory; Injury; Ischemia; Ischemic Preconditioning; Knockout Mice; Ligands; Link; MAPK14 gene; Mammals; Matrix Metalloproteinases; Mediating; Metabolic; Modeling; Morphine; NF-kappa B; Nerve Degeneration; Neurodegenerative Disorders; Neurosecretory Systems; Nitric Oxide; Ocular Hypertension; Opioid; Opioid Receptor; Optic Disk; Optic Nerve; Organ; Outcome; Pathway interactions; Patients; Pattern; Peptides; Physiological; Play; Production; Rattus; Receptor Activation; Retina; Retinal; Retinal Degeneration; Retinal Ganglion Cells; Risk Factors; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; Source; Stress; System; TNF gene; Testing; Tissues; Tumor Necrosis Factor-alpha; Vision; Visual impairment; Western Blotting; attenuation; base; bone morphogenetic protein 7; cell injury; cytokine; cytotoxic; effective therapy; immunocytochemistry; in vivo; mouse model; neuroprotection; optic nerve disorder; prevent; protective effect; public health relevance; receptor; research study; response

DESCRIPTION (provided by applicant): Glaucoma, one of the world's leading causes of visual impairment and blindness, is characterized by excavation of the optic nerve head and selective apoptotic loss of retinal ganglion cells (RGCs), resulting in a progressive decline in visual function. Nearly 67 million people worldwide are believed to have glaucoma, including an estimated 2.2 million in the USA. The etiology of the optic neuropathy is complex involving metabolic and biomechanical stress to the optic nerve head. The activation of astrocytes appears to have a central role in progressive optic neuropathy, serving as the cellular source of multifunctional cytokines and enzymes (matrix metalloproteinases [MMPs]) responsible for remodeling the extracellular matrix within the optic nerve head. In mammals, endogenous opioidergic peptides, such as enkephalins, dynorphins, and endorphins, are physiological modulators of neuroendocrine, immune, and inflammatory challenges that are released in response to stress. The effects of opioids are mediated through activation of three opioid receptor subtypes d, ?, and ¿. Under stressful conditions (e.g., ischemic, oxidative, and inflammatory stress), endogenous opioidergic peptides are released reducing stress-related injuries. In addition, activation of opioid-receptors by an exogenous agonist has been shown to elicit a protective effect during the situations of stress. Preliminary data presented in this application provide concrete evidence that: 1) administration of morphine in a chronic ocular-hypertensive rat model protected functional and structural integrity of RGCs; 2) activation of opioid receptors by endogenous ligands is required for the development of neuroprotection induced by ischemic preconditioning; and 3) Morphine inhibits production of tumor necrosis factor-a (TNF-a) and MMP-2 from both the ocular hypertension and acute ischemia rat models. Based on the new preliminary data, I hypothesize that opioid-receptor activation protects the optic nerve head and retinal ganglion cells from injury, in part, by suppressing the production and activity of inflammatory cytokines from ONH astrocytes. To test this hypothesis, three specific aims are proposed: Specific Aim 1: Determine if activation of specific opioid-receptor subtypes promotes retina neuroprotection in a chronic ocular-hypertension rat model. Specific Aim 2: Identify the signaling pathways modulated by d-opioid-receptors in human ONH astrocytes for attenuation of TNF-a and MMP production. Specific Aim 3: Ascertain that activation of d-opioid-receptor protects the retina against glaucomatous injury by suppressing TNF-a and MMP activity within the optic nerve head. Outcomes of this project will provide valuable leads in the discovery of more effective therapies that can delay or prevent vision loss associated with neurodegenerative diseases such as glaucoma. 5 PUBLIC HEALTH RELEVANCE: Glaucoma is one of the leading causes of blindness worldwide. Although, a major risk factor for the development of glaucoma is elevated IOP; the pathophysiological mechanisms by which elevated IOP leads to optic nerve atrophy and retina degeneration are unknown. Hence there is a need to develop neuroprotective strategies to prevent vision loss in the glaucomatous individual.

描述（由适用提供）：青光眼是世界视觉障碍和失明的主要原因之一，其特征是发掘视神经头部和视网膜神经节细胞的选择性凋亡丧失（RGC），导致视觉功能的逐渐下降。据信，全世界有近6700万人患有青光眼，其中包括美国220万人。视神经病变的病因是复杂的，涉及视神经头的代谢和生物力学应力。星形胶质细胞的激活似乎在进行性视神经病变中具有核心作用，它是负责重塑光学主管内的多功能细胞因子和酶（基质金属蛋白酶[MMPS]）的细胞来源。在哺乳动物中，内源性阿片类肽，例如恩基芬蛋白，dynorphins和内啡肽是神经内分泌，免疫和炎症性挑战的物理调节剂，这些调节剂响应压力而释放。阿片类药物的作用是通过激活三个阿片受体亚型d，？和`介导的。在应力条件下（例如缺血，氧化和炎症应激），内源性阿片类宠物被释放，以减少与压力相关的损伤。此外，已经证明，通过外源性激动剂激活阿片类药物受体会在压力情况下引起受保护的作用。本应用中提供的初步数据提供了具体的证据：1）在慢性眼 - 高血压大鼠模型中的施用吗啡保护RGC的功能和结构完整性； 2）通过缺血性预处理引起的神经保护需要通过内源配体激活阿片类药物受体； 3）吗啡抑制来自眼部高血压和急性缺血大鼠模型的肿瘤坏死因子A（TNF-A）和MMP-2的产生。根据新的初步数据，我假设阿片类药物受体激活可以通过抑制ONH星形胶质细胞的炎性细胞因子的产生和活性来保护视神经头和视网膜神经节细胞免受损伤。为了检验这一假设，提出了三个特定目的：具体目标1：确定特定阿片类药物受体亚型的激活是否在慢性眼 - 亚型大鼠模型中促进视网膜神经保护。具体目标2：确定人类ANH星形胶质细胞中D-阿片类受体调节的信号传导途径，以衰减TNF-A和MMP的产生。具体目标3：确定D-阿片类受体的激活通过抑制视神经头内的TNF-A和MMP活性来保护视网膜免受青光眼损伤。该项目的结果将为发现更有效的疗法提供宝贵的潜在客户，这些疗法可以延迟或防止与神经退行性疾病（如青光眼）相关的视力丧失。 5 公共卫生相关性：青光眼是全球失明的主要原因之一。虽然，青光眼发展的主要危险因素是IOP升高。升高IOP导致视神经萎缩和视网膜变性的病理生理机制尚不清楚。因此，有必要制定神经保护策略，以防止青光眼个体的视力丧失。