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

NEURITIN：新型RGC神经营养因子和青光眼治疗的潜在靶点

• 批准号: 7565586
• 负责人: Donald J. Zack
• 金额: $ 36.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7565586
• 关键词: Adult; Animal Model; Animals; Apoptosis; Axon; Axotomy; Blindness; Brain; Cell Death; Cell Survival; Cells; Complement; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Dependovirus; Development; Disease; Down-Regulation; Experimental Models; Eye; Gene Expression; Gene Expression Alteration; Gene Transfer; Genes; Glaucoma; Goals; Growth; Health; Human; In Situ Hybridization; In Vitro; Libraries; Maintenance; Mediating; Modeling; Molecular; Mus; Nerve Crush; Neurites; Optic Nerve; Optic Nerve Injuries; Pathogenesis; Pathway interactions; Phosphotransferases; Physiologic Intraocular Pressure; Physiological; Predisposition; Proteins; RNA Interference; Rattus; Retina; Retinal Ganglion Cells; Risk Factors; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Stress; Testing; Therapeutic; Therapeutic Studies; Time; United States; Work; axon regeneration; base; cell injury; chemical genetics; design; high throughput screening; in vivo; inhibitor/antagonist; insight; kinase inhibitor; neuroprotection; neurotrophic factor; new therapeutic target; novel; novel therapeutic intervention; optic nerve disorder; overexpression; pressure; public health relevance; research study; transcription factor; treatment strategy

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.

描述（由申请人提供）：青光眼是美国第二大致盲原因。了解视网膜神经节细胞（RGC）对变性的易感性是如何被主要危险因素，眼压（IOP）升高以及其他因素调节的，将有助于设计新的治疗方法来补充降低IOP。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一些与青光眼RGC死亡发病机制相关的细胞和基因表达改变。在表达失调的基因中，Neuritin1 （Nrn1）编码一种分泌因子，该因子对RGCs具有较强的神经保护和神经促进活性。我们假设NRN1是一种新的RGC衍生的神经营养因子，其IOP升高引发的RGC下调与青光眼RGC死亡的发生和进展有关。本研究将通过视神经应激动物模型来评价Nrn1在RGC神经保护和轴突再生中的治疗价值。在ai1中，我们将评估Nrn1是否需要维持成人RGC及其轴突网络，Nrn1是否可以保护RGC免受IOP升高引起的变性，以及当视神经受损时，Nrn1是否可以促进RGC轴突再生。在目的2中，我们将重点阐明Nrn1的表达如何受到上游信号通路和转录因子的调控。此外，还将评估这些调控机制在维持RGC存活方面的重要性。在目的3中，我们将探讨特异性激酶(s)在RGCs中NRN1信号转导的参与。通过完成上述研究，我们希望深入了解Nrn1表达受损如何导致RGC变性，以及Nrn1是否可以作为开发治疗青光眼和其他视神经病变的新型神经保护策略的靶点。公共卫生相关性：该项目的目标是了解视网膜神经节细胞（眼睛中负责将信息从眼睛传递到大脑的细胞）是如何死于青光眼的。我们将特别关注神经素-1因子。了解神经素-1在青光眼中的作用可能有助于了解该病的机制，并可能有助于开发新的治疗方法，以补充传统的降低眼压的方法。