FACTORS AFFECTING REGENERATION THROUGH THE GLIAL SCAR

影响胶质疤痕再生的因素

• 批准号: 2655451
• 负责人: Jerry Silver
• 金额: $ 20.44万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2655451
• 关键词: amyloid proteins; antibody; astrocytes; axon; cell adhesion; cell type; chick embryo; chondroitin sulfates; extracellular matrix; fibroblast growth factor; glia; gliosis; human tissue; hyaluronidase; immunochemistry; laboratory rat; nervous system regeneration; neurogenesis; neurons; neurotrophic factors; proteoglycan; scars; tissue /cell culture; transforming growth factors

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.

为了更好地了解中枢神经系统的胶质化伤口组织如何 被操纵以允许改进后续再生 中枢神经系统创伤或疾病，在此描述的实验目标 建议是了解触发星形胶质细胞的机制 变得反应性以及如何修饰星形胶质病以克服 反应性细胞产生的排斥元素。我们发现 将硝酸纤维素放在 新生大鼠皮层或用作体外底物触发的底物 有效神经突的反应性星形胶质细胞的合成增加 排斥软骨素硫酸盐蛋白聚糖（CS-PG）含有基质 该沉积在肽表面上。我们将使用这些 测试星形胶质细胞的区域和年龄特异性的测定 回应是否要了解来自各个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平均。我们将学习 各种细胞因子和营养因素是否可以改变 B-AP或其他潜力刺激的抑制性ECM产生 神经胶质病触发。软骨素酶或抗体的修饰 反应性星形胶质细胞和 在处理过或未处理的基质或顶部的神经元培养 反应性细胞本身将使我们能够确定。 反应性细胞或反应性基质可以支持鲁棒的轴突 一旦可疑抑制剂无效，生长就会产生。我们将净化 并在底物测定中表征B-AP诱导的胶质化基质 并将其与纯化的抑制性PG通过创伤诱导的体内诱导。 我们将生成针对最积极抑制的抗体 PG元素用于多种未来实验。实验 计划将反应性神经胶质基质抑制剂与 通过在两种再生模型中使用酶或抗体 胶质疤痕在体内。分子的识别和修饰 疤痕中的成分引起了耐磨性胶质化的生长 国家将使我们能够提出增强再生的策略 在神经胶质病是再生障碍的情况下。