Effects of Retinoic Acid Signaling on Retinal Ganglion Cell Survival and Regeneration

视黄酸信号传导对视网膜神经节细胞存活和再生的影响

• 批准号: 9212167
• 负责人: Rosa E. Blanco
• 金额: $ 11.25万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212167
• 关键词: Address; Adult; Affect; Agonist; Animals; Area; Axon; Axotomy; Blindness; Brain; Cell Survival; Cells; Data; Development; Diabetes Mellitus; Disease; Electron Microscopy; Excision; Gene Targeting; Genes; Glaucoma; Goals; Growth; Growth Factor; Injury; Investigation; Ischemia; Knowledge; Label; Lesion; Measures; Mediating; Medical; Methods; Microscope; Modeling; Molecular; Natural regeneration; Nerve Regeneration; Nervous system structure; Neuraxis; Neurites; Neuronal Differentiation; Neurons; Obstruction; Optic Nerve; Optic Nerve Injuries; Optics; Pathway interactions; Pattern; Peripheral Nerves; Pharmacology; Play; Process; Production; Proteins; Rana; Recovery; Research; Retinal; Retinal Ganglion Cells; Role; Sampling; Signal Pathway; Signal Transduction; Speed; Survival Rate; Synapses; Synaptic plasticity; Techniques; Tectum Mesencephali; Testing; Therapeutic; Tissues; Tretinoin; Vision; Visual system structure; Vitamin A; Western Blotting; Work; axon growth; axon regeneration; cell injury; design; experimental study; immunocytochemistry; improved; inhibitor/antagonist; injured; lipophilicity; nerve injury; nervous system development; neuronal survival; neurotrophic factor; neurotropin; novel therapeutic intervention; prevent; public health relevance; response; retinal axon; retinal regeneration; superior colliculus Corpora quadrigemina; Address; Adult; Affect; Agonist; Animals; Area; Axon; Axotomy; Blindness; Brain; Cell Survival; Cells; Data; Development; Diabetes Mellitus; Disease; Electron Microscopy; Excision; Gene Targeting; Genes; Glaucoma; Goals; Growth; Growth Factor; Injury; Investigation; Ischemia; Knowledge; Label; Lesion; Measures; Mediating; Medical; Methods; Microscope; Modeling; Molecular; Natural regeneration; Nerve Regeneration; Nervous system structure; Neuraxis; Neurites; Neuronal Differentiation; Neurons; Obstruction; Optic Nerve; Optic Nerve Injuries; Optics; Pathway interactions; Pattern; Peripheral Nerves; Pharmacology; Play; Process; Production; Proteins; Rana; Recovery; Research; Retinal; Retinal Ganglion Cells; Role; Sampling; Signal Pathway; Signal Transduction; Speed; Survival Rate; Synapses; Synaptic plasticity; Techniques; Tectum Mesencephali; Testing; Therapeutic; Tissues; Tretinoin; Vision; Visual system structure; Vitamin A; Western Blotting; Work; axon growth; axon regeneration; cell injury; design; experimental study; immunocytochemistry; improved; inhibitor/antagonist; injured; lipophilicity; nerve injury; nervous system development; neuronal survival; neurotrophic factor; neurotropin; novel therapeutic intervention; prevent; public health relevance; response; retinal axon; retinal regeneration; superior colliculus Corpora quadrigemina

 DESCRIPTION (provided by applicant): Effects of Retinoic Acid Signaling on Retinal Ganglion Cell Survival and Regeneration. Recovery of vision after optic nerve injury requires retinal ganglion cell (RGC) survival, axonal regrowth past the area of the lesion and reformation of appropriate synaptic targets. The adult mammalian visual system regenerates poorly, and past therapeutic efforts have enabled regrowth of only a small number of retinal axons. Frog RGCs, on the other hand, suffer an approximately 50% cell loss after injury, but regeneration and reconnection to target areas still occur because of the lack of inhibitory glial molecules and physical obstructions. This makes them a good model to explore which molecules influence RGC regeneration. Understanding what occurs after RGC injury is of great medical importance, because it results in blindness after optic nerve injury, and also in conditions such as glaucoma, diabetes and optic ischemia. The focus of the proposed work is to understand how the activity of retinoic acid (RA) signaling, known to exert effects on neurite outgrowth and homeostatic synaptic plasticity in the brain, affects the processes leading to recovery of vision after axotomy in the adult visual system. The aims of this proposal are to (1) determine the role of RA and the intracellular signaling pathways it activates in promoting RGC survival after injury, (2) determine the role of RA promoting regeneration of RGC axons, and (3) investigate the effects of RA on the reformation of synaptic connections in the retinorecipient layer of the optic tectum. The first aim will be accomplished by quantification of numbers of surviving RGCs, and Western blot analysis of regenerating retinal tissue. The second aim will be addressed by measuring the number of viable retinal axons crossing the lesion area, changes in the speed of regeneration, and changes in the abundance of GAP43 (regeneration marker) and NAV-2 (responsive gene in RA-mediated neurite outgrowth) in non-treated optic nerves and nerves from animals treated with RA signaling agonists and antagonists. The effect of RA signaling on the activation of relevant intracellular signaling pathways in regenerating RGCs will also be studied. The third aim will be carried out by quantifying anterogradely labeled retinal axons, the number of functional synaptic inputs, and the distribution of synaptic proteins in the retinorecipient layer f optic tectum after altering retinoic acid signaling and axotomy. Understanding the role of RA signaling in the response of retinal ganglion cells to nerve injury is important for the design of potential new therapeutic strategies.

 描述（由适用提供）：视黄酸信号传导对视网膜神经节细胞存活和再生的影响。视神经损伤后视力的恢复需要视网膜神经节细胞（RGC）的存活，轴突改革经过病变面积和识别适当的突触靶标。成年哺乳动物视觉系统的再生较差，过去的治疗努力仅能改革少量的视网膜轴突。另一方面，Frog RGC受伤后大约50％的细胞损失，但由于缺乏抑制性神经胶质分子和物理物体，还会发生再生和重新连接到目标区域。这使它们成为探索哪些分子影响RGC再生的好模型。了解RGC损伤后发生的事情至关重要，因为它会导致视神经损伤后的失明，以及在青光眼，糖尿病和视觉缺血等疾病中。拟议工作的重点是了解视黄酸（RA）信号传导的活性如何对大脑中神经蛋白的产物和稳态合成可塑性产生影响，会影响轴突切开术后视力恢复的过程 在成人视觉系统中。该建议的目的是（1）确定RA的作用以及它在促进受伤后促进RGC存活中激活的细胞内信号传导途径，（2）确定 RA促进RGC轴突再生的作用，以及（3）研究RA对视网膜视网膜层的突触连接的影响。第一个 AIM将通过数量的生存RGC和蛋白质印迹分析进行重生的视网膜组织来实现。第二个目标将通过测量越过病变区域的可行视网膜轴突的数量，再生速度的变化以及GAP43（再生标记）和NAV-2的抽象变化（RA介导的神经元介导的神经元介导的反应基因）在非诱因的光学神经和神经中，来自动物的神经和神经的神经，并用RAINGATION和RAINGATION攻击。 RA信号转导对再生RGC中相关细胞内信号通路的激活也将进行研究。第三个目的将通过量化星形标记的视网膜轴突，功能性突触输入的数量以及在改变视网膜酸信号传导和轴切开术后的视网膜交易层F光学构中的突触蛋白的分布。了解RA信号在视网膜神经节细胞对神经损伤反应中的作用对于设计潜在的新治疗策略很重要。