FACTORS AFFECTING REGENERATION THROUGH THE GLIAL SCAR

为了更好地了解中枢神经系统胶质损伤组织如何 被操纵，以允许改进以下再生 中枢神经系统创伤或疾病，本实验的目标是 建议是理解触发星形胶质细胞 变得反应性和如何修改星形胶质细胞增生症以克服 由反应细胞产生的排斥性元素。我们发现， 将不溶性B-淀粉样蛋白(B-AP)多肽放置在硝酸纤维素上 新生大鼠皮层或在体外用作底物时，触发 反应性星形胶质细胞促进强神经突起的合成 含有基质的排斥硫酸软骨素蛋白多糖(CS-PG) 它沉积在多肽的表面。我们将使用这些 检测星形胶质细胞的区域和年龄特异性的方法 反应了解来自不同区域的所有类型的星形胶质细胞 中枢神经系统对神经胶质触发的反应也是一样的。我们会研究 各种细胞因子和营养因子是否可以改变 B-AP或其他电位刺激的抑制性细胞外基质的产生 神经胶质增生症会引发。用软骨素酶或抗体进行修饰 反应性星形胶质细胞和基质中的抑制因子 神经细胞在处理或未处理的基质上或在其上的培养 反应细胞本身将允许我们确定。-是否 反应性细胞或反应性基质可以支持强健的轴突 一旦可疑的抑制剂被取消，就会产生后果。我们将净化 并在底物分析中鉴定了B-AP诱导的胶质细胞基质 并将其与创伤诱导的体内纯化抑制性PG进行比较。 我们将产生针对最活跃的抑制因子的抗体 PG元素，用于各种未来的实验。实验 计划用来使反应性胶质基质抑制剂无效 酶或抗体在两种再生模型中的使用 活体内的神经胶质疤痕。分子的鉴定和修饰 疤痕中导致生长难治性胶质细胞的成分 州政府将允许我们提出加强再生的战略 在胶质化是再生障碍的情况下。

In order to understand better how gliotic wound tissue of the CNS can be manipulated in order to allow for improved regeneration following CNS trauma or disease, the goals of the experiments described in this proposal are to understand the mechanisms that trigger astrocytes to become reactive and how to modify astrogliosis in order to overcome the repulsive elements made by reactive cells. We have discovered that insoluble B-amyloid (B-AP) peptides when placed on nitrocellulose into the neonatal rat cortex or when used as a substrate in vitro, trigger the increased synthesis by reactive astroglia of a potent neurite repulsive chondroitin sulfate proteoglycan (CS-PG) containing matrix that is deposited over the surface of the peptide. We will use these assays to test for regional and age specificity of the astroglial response to learn whether all types of astrocytes from various regions of the CNS respond equally to the gliotic trigger. We will study whether various cytokines and trophic factors can modify the production of inhibitory ECM stimulated by B-AP or other potential gliosis triggers. Modifications with chondroitinase or antibodies of the inhibitory factors in the matrix made by reactive astrocytes and culture of neurons on the treated or untreated matrix or on top of the reactive cells themselves will allow us to determine.-whether the reactive cells or the reactive matrix can support robust axonal outgrowth once the suspected inhibitor is nullified. We will purify and characterize in substrate assays the B-AP induced gliotic matrix and compare it to purified inhibitory PG's induced in vivo by trauma. We will generate antibodies specific to the most actively inhibitory PG elements for use in a variety of future experiments. Experiments are planned to nullify the reactive glial matrix inhibitor with the use of enzymes or antibodies in two models of regeneration through the glial scar in vivo. Identification and modification of the molecular components in the scar that give rise to the growth refractory gliotic state will allow us to suggest strategies for enhancing regeneration in situations where gliosis is a barrier to regeneration.