REGULATION OF FUNCTIONALLY REACTIVE GLIOSIS BY TGF-BETA

TGF-β 对功能反应性神经胶质增生的调节

• 批准号: 6393861
• 负责人: ROBERT J MCKEON
• 金额: $ 11.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6393861
• 关键词: Animalia; antireceptor antibody; astrocytes; axon; biological models; brain injury; carbohydrate biosynthesis; cell cell interaction; chondroitin sulfates; fibronectins; gliosis; growth factor receptors; laminin; nervous system regeneration; neurosurgery; neutralizing antibody; pathologic process; spinal cord injury; transforming growth factors

DESCRIPTION: The astrocytic response to CNS injury has long been implicated in the failure of damaged axons to regenerate beyond the injured area. Recent experiments have demonstrated that reactive astrocytes, originally considered physical barriers to regenerating axons produce an extracellular matrix (ECM) that inhibits axon outgrowth. In vitro assays suggest that the inhibitory component of this ECM is associated with the expression of chondroitin sulfate proteoglycans (CS-PGs) and that decreasing CS-PG expression after injury would enhance axonal regeneration through areas of reactive astrogliosis. CS-PGs are a group of complex molecules whose synthesis in a variety of peripheral cells is upregulated by transforming growth factor-beta (TGF-beta). The role of TGF-beta on CS-PG expression in the CNS is less clear. TGF-beta and CS-PG levels are highest in embryonic animals and both are downregulated shortly after birth. TGF-beta levels increase following CNS injury and this increase is correlated temporally and spatially with the re-expression of CS-PGs. Preliminary data demonstrate that in response to TGF-beta, cultured astrocytes synthesize a neurite growth inhibitory CS-PG and that this response is blocked by the addition of TGF-beta neutralizing antibodies. Data demonstrating that CS-PG expression is blocked after CNS injury by the in vivo administration of these TGF-beta neutralizing antibodies is now included. Based on these significant findings, it is hypothesized that TGF-beta stimulates CS-PG production after CNS injury and that neutralizing TGF-beta bioactivity will enhance axonal regeneration in vivo. These hypotheses will be tested by: ( 1 ) determining whether TGF-beta regulates the production of CS-PG after CNS injury by continuous intraventricular delivery of TGF-beta neutralizing antibodies and assessing CS-PG levels in the injured area; (2) examining the expression of specific CNS CS-PGs in response to TGF-beta, and; (3) examining whether neutralizing the function of TGF-beta enhances axonal regeneration following spinal cord injury. These studies will help identify signals that stimulate the production of axon growth inhibitory CS-PGs by reactive astrocytes. Decreasing the expression of these inhibitory molecules, combined with the use of factors known to promote axon outgrowth, may lead to the development of comprehensive strategies designed to optimize axonal regeneration after CNS injury.

描述：长期以来，星形胶质细胞对中枢神经系统损伤的反应已经 与受损的轴突未能再生的失败有关 受伤区域。最近的实验证明了反应性 星形胶质细胞最初被认为是重生的物理障碍 轴突产生细胞外基质（ECM），该基质抑制轴突 出生。 体外测定表明 该ECM与硫酸软骨素的表达有关 蛋白聚糖（CS-PGS），损伤后CS-PG表达降低 将通过反应性区域增强轴突再生 星形胶质病。 CS-PG是一组复杂分子的合成 在各种外围细胞中，通过转化生长上调 因子 - 贝塔（TGF-beta）。 TGF-beta在CS-PG表达中的作用 中枢神经系统不太清楚。 TGF-β和CS-PG水平在胚胎中最高 动物和两者出生后不久都被下调。 TGF-β级别 中枢神经系统损伤后增加，这种增加在时间上相关 并在CS-PG的重新表达中空间表达。 初步数据 证明为响应TGF-beta，培养的星形胶质细胞合成 神经突生长抑制性CS-PG，这种反应被阻止 TGF-β中和抗体的添加。数据证明 CS-PG表达在CNS损伤后被体内阻塞 这些TGF-β中和抗体的给药是 包括。 基于这些重要发现，可以假设 TGF-β刺激CNS损伤后CS-PG的产生，并且 中和TGF-β生物活性将增强轴突再生 体内。 这些假设将通过：（1）确定是否是否 TGF-beta调节CNS损伤后CS-PG的产生 TGF-β中和抗体的连续脑室室内递送 并评估受伤区域的CS-PG水平； （2）检查 响应TGF-beta的特定CNS CS-PG的表达，并且； （3） 检查中和TGF-β的功能是否增强了轴突 脊髓损伤后的再生。这些研究将有助于 确定刺激轴突生长抑制作用的信号 反应性星形胶质细胞的CS-PG。 减少这些表达 抑制分子，结合使用已知促进的因子 轴突的生长，可能导致制定综合策略 旨在优化CNS损伤后的轴突再生。