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损害和失明的主要原因之一，其特征是视神经头的挖掘和视网膜神经节细胞（RGCs）的选择性凋亡损失，导致视觉功能的进行性下降。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。视神经病变的病因复杂，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起核心作用，作为多功能细胞因子和酶（基质金属蛋白酶[MMPs]）的细胞来源，负责重塑视神经头内的细胞外基质。在哺乳动物中，内源性阿片能肽，如脑啡肽、动啡肽和内啡肽，是神经内分泌、免疫和炎症挑战的生理调节剂，在应激反应中释放。阿片受体的作用是通过激活三种阿片受体亚型d， ？，和¿？在应激条件下（如缺血、氧化和炎症应激），内源性阿片能肽被释放，减轻应激相关损伤。此外，通过外源性激动剂激活阿片受体已被证明在应激情况下可引起保护作用。本研究提供的初步数据提供了具体证据：1)吗啡对慢性眼高血压大鼠模型RGCs的功能和结构完整性有保护作用；2)内源性配体激活阿片受体是缺血预处理诱导的神经保护发生的必要条件；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星形胶质细胞炎症细胞因子的产生和活性。为了验证这一假设，提出了三个特定目的：特定目的1：确定慢性眼压大鼠模型中特定阿片受体亚型的激活是否促进视网膜神经保护。特异性目标2：确定人类ONH星形细胞中d-阿片受体调节的信号通路，以抑制TNF-a和MMP的产生。特异性目的3：确定d-阿片受体的激活通过抑制视神经头内TNF-a和MMP的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，这些治疗方法可以延缓或预防与青光眼等神经退行性疾病相关的视力丧失。5

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