Opioidergic System: Its Role(s) in Glaucoma

描述（由申请人提供）：青光眼是世界上视力损害和失明的主要原因之一，其特征在于视神经乳头的凹陷和视网膜神经节细胞（RGC）的选择性凋亡损失，导致视觉功能的进行性下降。据信，全世界有近6700万人患有青光眼，其中估计美国有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，作为多功能细胞因子和酶（基质金属蛋白酶[MMP]）的细胞来源，负责重塑视神经乳头内的细胞外基质。 在哺乳动物中，内源性阿片肽，如脑啡肽、强啡肽和内啡肽，是响应于应激而释放的神经内分泌、免疫和炎症挑战的生理调节剂。阿片类药物的作用是通过激活三种阿片受体亚型d，和。在压力条件下（例如，缺血性、氧化性和炎性应激）时，释放内源性阿片样肽，减少应激相关损伤。此外，外源性激动剂对阿片受体的激活已显示在应激情况下引起保护作用。 本申请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施用吗啡保护RGCs的功能和结构完整性; 2）通过内源性配体激活阿片受体是由缺血预处理诱导的神经保护的发展所需的;吗啡抑制高眼压和急性缺血大鼠模型中肿瘤坏死因子-α（TNF-α）和MMP-2的产生。基于新的初步数据，我假设阿片受体激活保护视神经乳头和视网膜神经节细胞免受损伤，部分是通过抑制ONH星形胶质细胞炎性细胞因子的产生和活性。为了验证这一假设，提出了三个具体目标：具体目标1：确定是否激活特定的阿片受体亚型促进视网膜神经保护在慢性高眼压大鼠模型。 具体目的2：鉴定人ONH星形胶质细胞中由d-阿片样物质受体调节的信号传导途径，以减弱TNF-α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乳头内的TNF-α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治疗方法提供有价值的线索，这些方法可以延迟或预防与青光眼等神经退行性疾病相关的视力丧失。5 与公共卫生的相关性：青光眼是全球范围内导致失明的主要原因之一。尽管青光眼发展的主要风险因素是IOP升高;但IOP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。因此，有必要开发神经保护策略，以防止视力丧失的昏迷的个人。

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.