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

 描述（由申请人提供）：本研究的长期目标是阐明衰老和眼内压（IOP）如何影响青光眼视网膜神经节细胞（RGC）变性，并利用这些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动作电位编码的，这些动作电位沿着沿着RGC轴突在视觉投射中传播。这些轴突从成年期到死亡期间稳定退化，并且在青光眼早期易受影响。轴突信号主要由兴奋性谷氨酸能突触决定，这些突触在RGC树枝状结构中相加和整合。本研究的目的是了解老年人和青光眼视神经投射中的RGC轴突变性与视网膜中突触退化的关系。为了获得这种理解，实验将测试一个新的中心假设：由于老化和IOP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传导，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设形成鲜明对比，在该假设中，早期和不可撤销的突触和树突修剪驱动RGC轴突损失。一系列严格的、定量的和功能性的测定将通过利用青光眼的慢性（DBA2J）和诱导型（微珠阻塞）模型来测试这种重塑假设。目标1中的实验将改变IOP，并将突触和细胞骨架组分的变化映射到不同RGC类型的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类型的突触和树突变化如何取决于年龄以及年龄是否影响对升高的IOP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体细胞变性，并确定关键年龄和IOP，单个RGC类型中的树突和突触是否是保守的或独立地进行重塑。这些结合神经化学、形态学和生理学措施的创新研究将丰富对突触和轴突活动如何在分子水平上相互关联的理解，并为基于神经元自我修复的新型疗法奠定基础。

 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.