Influence of cell adhesion molecules on neuron survial and plasticity in the adult central nervous system

更详细地了解影响中枢神经系统(CNS)神经元存活的机制，对于未来了解神经元对损伤的反应是至关重要的。啮齿动物的视觉系统为研究视网膜神经节细胞(RGCs)的生存提供了一个通用的模型，RGC是视网膜内的CNS神经元，最近的研究表明，神经细胞黏附分子(NCAM)及其多唾液酸化形式(PSA-NCAM)可能介导神经元的存活。NCAM和PSA-NCAM都参与了细胞发育和再生的各种功能。NCAM是一种细胞表面蛋白，PSA是一种仅定位于NCAM的碳水化合物。一些研究表明，刺激NCAM结合可以提高神经元的存活，而去除PSA则通过凋亡促进神经元死亡。尽管NCAM和PSA-NCAM在视网膜中大量表达，但它们在成人中的功能尚不清楚。然而，这两个分子都表达在视网膜外植体的再生纤维上，提示可能在再生中发挥作用。因此，视网膜为评估NCAM和PSA-NCAM在受损RGCs生存中的作用提供了一个很好的范例。本课题的目的是评价NCAM和PSA-NCAM在调节RGC存活中的作用。具体来说，我们提出以下问题：(1)NCAM和PSA-NCAM在损伤后的视觉系统中的表达是否发生变化；(2)NCAM和PSA-NCAM的缺失是否影响未损伤和受损RGC的存活；以及(3)NCAM和PSA-NCAM调节RGC存活的机制是什么？

A more detailed knowledge of the machanisms that influence neuronal survival in the central nervous system (CNS) is imperative to the future understanding of how neurons respond to injury.  The rodent visual system provides a versatile model for studying the survival of retinal ganglion cells (RGCs), which are CNS neurons within the retina, as well as for evaluating the effectiveness of pharmacotherapies and surgical interventions following injury.   Recent studies have indicated that the neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) may mediate neuronal survival.  NCAM and PSA-NCAM both have been implicated in various functions of cellular development and regeneration.  NCAM is a cell surface protein and PSA is a carbohydrate localized exclusively on NCAM.  Several studies indicate that stimulation of NCAM binding enhances neuronal survival while PSA removal promotes neuronal death via apoptosis. Despite abundant expression of NCAM and PSA-NCAM in the retina, their functions in the adult remain unknown.  However, both molecules are expressed on regenerating fibers of retinal explants, suggesting a possible role in regeneration.  The retina, therefore, provides an excellent paradigm to evaluate the role of NCAM and PSA-NCAM in the survival of injured RGCs. The aim of this project is to evaluate the role of NCAM and PSA-NCAM in mediating the survival of RGCs.  Specifically, we are asking the following questions: (1) are NCAM and PSA-NCAM expression altered in the visual system following injury; (2) is the survival of uninjured and injured RGCs influenced by the absence of NCAM and PSA; and (3) what are the mechanisms by which NCAM and PSA-NCAM mediate RGC survival?