NEURITIN:novel RGC neurotrophic factor and potential target for glaucoma therapy

描述(申请人提供)：青光眼是美国第二大致盲原因。了解视网膜神经节细胞(RGC)对变性的易感性如何受到主要危险因素--眼压升高以及其他因素的调节，将有助于设计新的治疗方法来补充眼压降低。通过研究青光眼和视神经损伤的实验模型，我们和其他人已经确定了与青光眼RGC死亡的发病机制相关的一些细胞和基因表达的变化。在表达异常的基因中，Neuritin1(Nrn1)编码一种分泌因子，对视网膜节细胞具有很强的神经保护和促进轴突生长的活性。我们假设NRN1是一种新的RGC源性神经营养因子，其眼压升高引发的RGC下调与青光眼RGC死亡的发生和发展有关。本研究将利用视神经应激动物模型评价Nrn1在RGC神经保护和轴突再生中的治疗价值。在AIM 1中，我们将评估Nrn1是否是维持成年视网膜节细胞及其轴突网络所必需的，Nrn1是否能保护视网膜节细胞免受眼压升高引起的变性，以及在视神经受损时是否能促进视网膜节细胞轴突的再生。在AIM2中，我们将重点阐明Nrn1的表达如何受到上游信号通路(S)和转录因子的调控。此外，将评估这些调控机制在维持研资局生存方面的重要性。在AIM 3中，我们将探讨特异性激酶(S)在视网膜节细胞NRN1信号转导中的作用。通过完成上述研究，我们希望深入了解Nrn1表达受损是如何导致RGC变性的，以及NRN1是否可以作为开发治疗青光眼和其他视神经疾病的新的神经保护策略的靶点。与公共卫生相关：该项目的目标是了解视网膜神经节细胞是如何在青光眼疾病中死亡的。视网膜神经节细胞是眼睛中将信息从眼睛传递到大脑的细胞。我们将特别关注神经素-1因子。了解神经素-1‘S在青光眼中的作用可能有助于深入了解青光眼的发病机制，并可能有助于开发新的治疗方法来补充传统的降眼压方法。

DESCRIPTION (provided by applicant): Glaucoma is the second leading cause of blindness in the United States. Understanding how retinal ganglion cell (RGC) susceptibility to degeneration is modulated by the major risk factor, elevation of intraocular pressure (IOP), as well as other factors, will help in designing novel therapeutic approaches to complement IOP lowering. By studying experimental models of glaucoma and optic nerve injury, we and others have determined some of the cellular and gene expression alterations associated with the pathogenesis of glaucomatous RGC death. Among the genes whose expression is dysregulated, Neuritin1 (Nrn1) encodes a secreted factor that possesses strong neuroprotective and neurite-promoting activities on RGCs. We hypothesize that NRN1 is a novel RGC-derived neurotrophic factor whose IOP elevation- triggered downregulation in RGCs is associated with the onset and progression of RGC death in glaucoma. In this study, the therapeutic value of Nrn1 in RGC neuroprotection and axon regeneration will be evaluated with animal models of optic nerve stress. In aim1, we will assess whether Nrn1 is required for the maintenance of adult RGCs and their axonal network, whether Nrn1 can protect RGC from IOP elevation- induced degeneration, and whether it can promote RGC axon regeneration when the optic nerve is damaged. In aim2, we will focus on elucidating how Nrn1 expression is regulated by upstream signal pathway(s) and transcription factors. Moreover, the importance of these regulatory mechanisms in maintaining RGC survival will be evaluated. In aim3, we will explore the involvement of specific kinase(s) in the signal transduction of NRN1 in RGCs. By accomplishing the above proposed studies, we hope to gain insight into how impaired Nrn1 expression contributes to RGC degeneration and whether NRN1 could serve as a target for the development of novel neuroprotective strategies for the treatment of glaucoma and other optic neuropathies. PUBLIC HEALTH RELEVANCE: The goal of this project is to understand how retinal ganglion cells, the cells in the eye that transmit information from the eye to the brain, die in the disease glaucoma. We will specifically focus on the factor neuritin-1. Understanding neuritin-1's role in glaucoma may provide insights into the mechanisms of the disease, and may help to develop new treatment approaches to complement the traditional approach of eye pressure lowering.