Mechanisms of Synaptic Remodeling and Neuronal Self-Repair in Aging and Glaucoma

衰老和青光眼中突触重塑和神经元自我修复的机制

• 批准号: 9181431
• 负责人: David J. Calkins
• 金额: $ 39.5万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-02 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181431
• 关键词: Action Potentials; Address; Adult; Age; Aging; Apoptotic; Axon; BAX gene; Biological Assay; Blindness; Brain; Cells; Cessation of life; Chronic; Complement; Complex; Dendrites; Dendritic Cells; Dependence; Disease; Excitatory Synapse; Foundations; Functional disorder; Glaucoma; Glutamates; Goals; Individual; Knock-out; Knowledge; Laboratories; Longevity; Maps; Measures; Mediating; Microspheres; Modeling; Molecular; Morphology; Mus; Natural regeneration; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Optic Disk; Optic Nerve; Optics; Patients; Pattern; Physiologic Intraocular Pressure; Physiological; Process; Proteins; Regimen; Research; Retina; Retinal; Retinal Degeneration; Retinal Ganglion Cells; Risk Factors; Series; Signal Transduction; Stress; Sum; Synapses; System; Testing; Therapeutic Intervention; Tissues; Transgenes; Transgenic Organisms; Vision; Wallerian Degeneration; Work; age related; aged; aging brain; axonal degeneration; axonopathy; base; cell type; density; experimental study; glutamatergic signaling; innovation; mouse model; neurochemistry; neurotransmission; normal aging; novel; novel therapeutics; optic nerve disorder; pressure; public health relevance; repaired; response; retinotopic; synaptogenesis; targeted treatment; tool

 DESCRIPTION (provided by applicant): The long-term goal of this research is to elucidate how aging and intraocular pressure (IOP) influence retinal ganglion cell (RGC) degeneration in glaucoma and to leverage this knowledge to identify novel therapies based on neuronal protection, repair, and regeneration. This is an important goal, since all of vision is encoded by action potentials propagated along RGC axons in the optic projection. These axons degenerate steadily from adulthood to death and are susceptible early in glaucoma. Axonal signals are determined primarily by excitatory, glutamatergic synapses summed and integrated in the RGC dendritic arbor. The objective here is focused on understanding how RGC axon degeneration in the optic projection in aging and glaucoma relates to synapse degradation in the retina. To gain this understanding, experiments will test a novel central hypothesis: that early axonal stress due to aging and IOP induces self-repair and adaptive remodeling of the RGC synaptic complex to prolong signaling, similar to homeostatic plasticity of excitatory synapses in other systems. This dynamic relationship stands in stark contrast to the most prevalent current hypothesis in which early and irrevocable synaptic and dendritic pruning drives RGC axon loss. A series of rigorous, quantitative and functional assays will test this remodeling hypothesis by leveraging both chronic (DBA2J) and inducible (microbead occlusion) models of glaucoma. Experiments in Aim 1 will vary IOP and map changes in synaptic and cytoskeletal components to dendritic complexity and axonal function for different RGC types. Aim 2 will assess how synaptic and dendritic changes for RGC types characterized by axon function depend on age and whether aging influences the response to elevated IOP. Finally, Aim 3 will use established transgenic tools to modulate axonal and somatic degeneration and determine for key ages and IOPs whether dendrites and synapses in individual RGC types are conserved or undergo remodeling independently. These innovative studies combining neurochemical, morphological, and physiological measures will enrich the understanding of how synaptic and axonal activity interrelate at the molecular level and lay the foundation for novel therapeutics based on neuronal self-repair.

 描述（由适用提供）：这项研究的长期目标是阐明青光眼中的衰老和眼内压（IOP）如何影响残留的神经节细胞（RGC）变性，并利用这些知识来识别基于神经元保护，修复和再生的新型治疗方法。这是一个重要的目标，因为所有视觉均由沿RGC轴突传播的动作电位编码。这些轴突从成人到死亡稳步退化，在青光眼早期易感。轴突信号是通过兴奋性，谷氨酸能突触的夏季来确定的，并集成在RGC树突状乔木中。此处的目的是理解老化和青光眼的视频投影中的RGC轴突变性与视网膜中的突触降解有关。为了获得这种理解，实验将检验一个新的中心假设：由于衰老和IOP引起的早期轴突应激会诱导RGC合成复合物的自我修复和适应性重塑以延长其他系统中兴奋突触的稳态可塑性的延长信号传导。这种动态关系与最普遍的当前假设形成了鲜明的对比，在这种假设中，早期和不可撤销的突触和树突状修剪驱动RGC轴突损失。一系列严格的，定量和功能测定将通过利用青光眼的慢性（DBA2J）和诱导型（Microbead遮挡）模型来检验这种重塑假设。 AIM 1中的实验将变化IOP，并将突触和细胞骨架成分的变化变化为不同RGC类型的树突复杂性和轴突函数。 AIM 2将评估由轴突功能为特征的RGC类型的合成和树突变化取决于年龄以及衰老是否影响对IOP升高的响应。最后，AIM 3将使用已建立的转基因工具来调节轴突和体细胞变性，并确定关键年龄和IOPS和IOPS是否保守或独立进行重塑。这些创新的研究结合了神经化学，形态学和物理措施，将丰富对合成和轴突活性如何在分子水平相互关联的理解，并为基于神经元自我修复的新型治疗奠定基础。