Axons and the Extracellular Matrix in Spinal Cord Injury

描述（由申请人提供）：成年哺乳动物脊髓损伤（SCI）后，脊髓内的祖细胞和星形胶质细胞分裂并迁移到病变部位的边缘，在那里它们经历肥大并改变其基因和蛋白质表达模式。这些反应有助于形成致密的神经胶质边界，这限制了炎症损伤的扩大，但也对轴突生长和再生产生了障碍。本研究计划的长期目标是了解胶质瘢痕形成的潜在机制，并确定改变这种细胞反应的方法，以改善脊髓修复的前景。核心假设是，存在于成年脊髓中的脊髓祖细胞和星形胶质细胞是动态细胞，它们对局部线索作出反应以改变它们的行为。因此，在适当刺激的存在下，这些细胞可以被招募为修复的积极参与者，并且可以被刺激以支持损伤后生长的轴突。先前的研究表明，转化生长因子α（TGF α）可以刺激祖细胞和星形胶质细胞的增殖和迁移，并将星形胶质细胞转化为生长支持表型。本提案的目的是确定是否有针对性地激活表皮生长因子受体与TGF-1将增强胶质细胞生成，神经保护和星形胶质细胞迁移，并建立这些反应是否可以被利用来诱导形成允许的细胞桥，将支持轴突生长后SCI。目标1中的研究将使用功能丧失和功能获得方法来检验EGFR激活促进胶质细胞生成并增强SCI后神经保护的假设。在目标2中，EGFR激活将与再生方法相结合，以检验TGF β 1过表达可以促进SCI后生长支持性胶质桥形成的假设。最后，目标3将采用体外和体内研究来确定TGF 1的作用是否受到急性和慢性SCI中炎症变化的调节。这些目标的实现将明确EGFR活化在损伤后胶质可塑性和神经修复中的作用。这些结果将提供有关损伤部位周围细胞功能的重要信息，并作为未来减少组织损失和支持SCI后轴突生长的联合策略的重要组成部分。

DESCRIPTION (provided by applicant): After spinal cord injury (SCI) in adult mammals, progenitor cells and astrocytes within the spinal cord divide and migrate to the edge of the lesion site, where they undergo hypertrophy and alter their patterns of gene and protein expression. These responses contribute to formation of a dense glial border, which limits the expansion of inflammatory damage, but also creates a barrier to axonal growth and regeneration. The long term goal of this research program is understand the underlying mechanisms of glial scar formation and identify ways to modify this cellular response in order to improve the prospect of spinal cord repair. The central hypothesis is that spinal cord progenitor cells and astrocytes present in the adult spinal cord are dynamic cells that respond to local cues to change their behavior. Thus, in the presence of an appropriate stimulus, these cells can recruited as active participants for repair and can be stimulated to support growing axons after injury. Prior studies have shown that transforming growth factor alpha (TGFa) can stimulate the proliferation and migration of progenitor cells and astrocytes, and transform astrocytes to a growth supportive phenotype. The objective of this proposal is to determine if targeted activation of the epidermal growth factor receptor with TGF1 will enhance gliogenesis, neuroprotection, and astrocyte migration, and to establish if these responses can be exploited to induce the formation of permissive cellular bridges that will support axonal growth following SCI. The studies in Aim 1 will use loss of function and gain of function approaches to test the hypothesis that EGFR activation facilitates gliogenesis and enhances neuroprotection after SCI. In Aim 2, EGFR activation will be combined with regenerative approaches to test the hypothesis that TGF1overexpression can facilitate the formation of growth supportive glial bridges after SCI. Finally, Aim 3 will employ in vitro and in vivo studies to determine if the effects of TGF1 are modulated by changes in inflammation in acute and chronic SCI. Completion of these aims will define the roles of EGFR activation in glial plasticity and neural repair after injury. These results will provide essential information about the function of cells surrounding the lesion site and serve as an important part of future combination strategies to reduce tissue loss and support axonal growth after SCI.