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.

为了更好地理解中枢神经系统的神经胶质创伤组织如何能够 以便允许改进的再生， 中枢神经系统创伤或疾病，本文中描述的实验的目标是 我们的建议是了解触发星形胶质细胞的机制， 以及如何改变星形胶质细胞增生以克服 由反应性细胞产生的排斥性元素。我们发现 当将不溶性B-淀粉样蛋白（B-AP）肽置于硝酸纤维素上时， 新生大鼠皮层或当用作体外底物时， 反应性星形胶质细胞合成的强神经突 含有排斥性硫酸软骨素蛋白聚糖（CS-PG）的基质 沉积在肽的表面。我们将会用这些 用于测试星形胶质细胞的区域和年龄特异性的测定 以了解来自不同区域的所有类型的星形胶质细胞是否 对神经胶质触发物的反应是一样的我们将研究 各种细胞因子和营养因子是否可以改变 由B-AP或其他潜在刺激产生抑制性ECM 神经胶质增生的诱因用软骨素酶或抗体修饰 反应性星形胶质细胞产生的基质中的抑制因子， 在经处理或未经处理的基质上或在 反应细胞本身可以让我们确定。是否 反应性细胞或反应性基质可以支持强大的轴突 一旦可疑的抑制剂被消除，就会产生新的生长。我们将净化 并在底物测定中表征B-AP诱导的神经胶质基质 并将其与由创伤在体内诱导的纯化的抑制性PG进行比较。 我们将产生抗体， PG元素用于各种未来的实验。实验 计划用免疫抑制剂来消除反应性胶质基质抑制剂， 酶或抗体在两种再生模型中的应用， 胶质瘢痕。分子鉴定和修饰 瘢痕中引起生长难治性神经胶质瘤的成分 国家将允许我们提出加强再生的战略， 在神经胶质增生是再生障碍的情况下。