Opioidergic System: Its Role(s) in Glaucoma

阿片类药物系统：其在青光眼中的作用

基本信息

批准号：
7987358
负责人：
Shahid Husain
金额：
$ 36.88万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
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/7987358
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 Tumor Necrosis Factors 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

项目摘要

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（由申请人提供）：青光眼是世界上导致视力障碍和失明的主要原因之一，其特征是视神经乳头凹陷和视网膜神经节细胞（RGC）选择性凋亡丧失，导致视功能进行性下降据信全世界有近 6700 万人患有青光眼，其中美国估计有 220 万人。视神经病变的病因很复杂，涉及代谢和疾病。星形胶质细胞的激活似乎在进行性视神经病变中起着核心作用，是负责重塑视神经内细胞外基质的多功能细胞因子和酶（基质金属蛋白酶 [MMP]）的细胞来源。在哺乳动物中，内源性阿片肽，例如脑啡肽、强啡肽和内啡肽，是神经内分泌、免疫、阿片类药物的作用是通过激活三种阿片受体亚型 d、? 和 ¿ 来介导的。在应激条件下（例如，缺血、氧化和炎症应激），内源性阿片肽被释放，减少应激相关损伤。此外，外源性激动剂激活阿片受体已被证明可以在应激情况下产生保护作用。本申请中提供的初步数据提供了具体证据：1)在慢性高眼压大鼠模型中施用吗啡可以保护RGC的功能和结构完整性； 2) 缺血预适应诱导的神经保护作用需要内源性配体激活阿片受体；3) 吗啡抑制高眼压和急性缺血产生的肿瘤坏死因子-a (TNF-a) 和 MMP-2根据新的初步数据，我认为阿片受体激活可以部分通过抑制其产生和活动来保护视神经乳头和视网膜神经节细胞免受损伤。为了检验这一假设，提出了三个具体目标：具体目标 1：确定特定阿片受体亚型的激活是否会促进慢性高眼压大鼠模型的视网膜神经保护。人 ONH 星形胶质细胞中 d-阿片受体调节的途径，用于减弱 TNF-a 和 MMP 的产生。具体目标 3：确定d-阿片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有价值的线索，这些疗法可以延迟或预防相关的视力丧失。患有青光眼等神经退行性疾病5。公众健康相关性：青光眼是全球失明的主要原因之一，尽管眼压升高是青光眼发生的一个主要危险因素，但眼压升高导致视神经萎缩和视网膜变性的病理生理机制尚不清楚。需要制定神经保护策略来防止青光眼患者视力丧失。