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

 描述(申请人提供)：这项研究的长期目标是阐明衰老和眼压(IOP)如何影响青光眼患者的视网膜神经节细胞(RGC)变性，并利用这一知识来确定基于神经元保护、修复和再生的新疗法。这是一个重要的目标，因为所有的视觉都是由沿着视觉投射中的RGC轴突传播的动作电位编码的。这些轴突从成年期逐渐退化到死亡，在青光眼早期很容易受到影响。轴突信号主要由兴奋性谷氨酸能突触决定，这些突触汇总并整合在RGC树突中。这里的目的是了解衰老和青光眼视神经投射中的RGC轴突变性与视网膜突触退化的关系。为了了解这一点，实验将检验一个新的中心假说：由于衰老和眼压而导致的早期轴突应激诱导RGC突触复合体的自我修复和适应性重塑，以延长信号，类似于其他系统中兴奋性突触的稳态可塑性。这种动态关系与当前最流行的假说形成鲜明对比，在该假说中，早期不可撤销的突触和树突修剪导致RGC轴突丢失。一系列严格的、定量的和功能性的分析将通过利用慢性(DBA2J)和诱导性(微珠阻塞)青光眼模型来检验这一重塑假说。目标1中的实验将针对不同的RGC类型改变眼压，并将突触和细胞骨架成分的变化映射到树突复杂性和轴突功能。目的2将评估以轴突功能为特征的RGC类型的突触和树突的变化如何依赖于年龄，以及年龄是否影响对高眼压的反应。最后，Aim 3将使用已建立的转基因工具来调节轴突和躯体退行性变，并确定关键年龄和眼压的关键年龄和眼压是否个别RGC类型的树突和突触是保守的或独立重塑。这些结合了神经化学、形态学和生理学方法的创新性研究将在分子水平上丰富对突触和轴突活动相互关系的理解，并为基于神经元自我修复的新型治疗方法奠定基础。

 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.