Opioidergic System: Its Role(s) in Glaucoma

描述(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，其特征是视神经头被挖出，视网膜神经节细胞(RGC)选择性凋亡丢失，导致视觉功能进行性下降。全世界有近6700万人被认为患有青光眼，其中美国估计有220万人。视神经病变的病因是复杂的，涉及到视神经头的代谢和生物力学应激。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，是多功能细胞因子和酶(基质金属蛋白酶[MMPs])的细胞来源，这些酶负责重塑视神经头内的细胞外基质。在哺乳动物中，内源性阿片肽，如脑啡肽、强啡肽和内啡肽，是神经内分泌、免疫和炎症挑战的生理调节剂，这些挑战在应激反应中被释放。阿片类药物的作用是通过激活三种阿片受体亚型d、？和？来实现的。在应激条件下(如缺血、氧化和炎症应激)，内源性阿片肽被释放，减少应激相关的损伤。此外，外源性激动剂激活阿片受体在应激状态下也能产生保护作用。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给予吗啡，保护了视网膜节细胞的功能和结构完整性；2)阿片受体由内源性配体激活，是缺血预适应诱导的神经保护所必需的；以及3)吗啡抑制高眼压和急性缺血大鼠模型中肿瘤坏死因子-a(TNF-a)和基质金属蛋白酶-2的产生。根据新的初步数据，我假设阿片受体激活保护视神经头和视网膜神经节细胞免受损伤，部分是通过抑制ONH星形胶质细胞产生和活性炎性细胞因子来实现的。为了验证这一假设，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促进了慢性高眼压大鼠模型的视网膜神经保护。具体目标2：确定人ONH星形胶质细胞中受d-阿片受体调控的信号通路，以减少肿瘤坏死因子-α和基质金属蛋白酶的产生。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肿瘤坏死因子-a和基质金属蛋白酶的活性来保护视网膜免受青光眼的损伤。该项目的成果将为发现更有效的疗法提供宝贵的线索，这些疗法可以延缓或防止与青光眼等神经退行性疾病相关的视力丧失。5. 与公共卫生相关：青光眼是世界范围内导致失明的主要原因之一。然而，青光眼发生的一个主要危险因素是高眼压；高眼压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，有必要开发神经保护策略来预防青光眼患者的视力丧失。

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.