The extracellular matrix is a richly bioactive composition of substrates that provides biophysical stability, facilitates intercellular signaling, and both reflects and governs the physiological status of the local microenvironment. The matrix in the central nervous system (CNS) is far from simply an inert scaffold for mechanical support, instead conducting an active role in homeostasis and providing broad capacity for adaptation and remodeling in response to stress that otherwise would challenge equilibrium between neuronal, glial, and vascular elements. A major constituent is collagen, whose characteristic triple helical structure renders mechanical and biochemical stability to enable bidirectional crosstalk between matrix and resident cells. Multiple members of the collagen superfamily are critical to neuronal maturation and circuit formation, axon guidance, and synaptogenesis in the brain. In mature tissue, collagen interacts with other fibrous proteins and glycoproteins to sustain a three-dimensional medium through which complex networks of cells can communicate. While critical for matrix scaffolding, collagen in the CNS is also highly dynamic, with multiple binding sites for partnering matrix proteins, cell-surface receptors, and other ligands. These interactions are emerging as critical mediators of CNS disease and injury, particularly regarding changes in matrix stiffness, astrocyte recruitment and reactivity, and pro-inflammatory signaling in local microenvironments. Changes in the structure and/or deposition of collagen impact cellular signaling and tissue biomechanics in the brain, which in turn can alter cellular responses including antigenicity, angiogenesis, gliosis, and recruitment of immune-related cells. These factors, each involving matrix collagen, contribute to the limited capacity for regeneration of CNS tissue. Emerging therapeutics that attempt to rebuild the matrix using peptide fragments, including collagen-enriched scaffolds and mimetics, hold great potential to promote neural repair and regeneration. Recent evidence from our group and others indicates that repairing protease-degraded collagen helices with mimetic peptides helps restore CNS tissue and promote neuronal survival in a broad spectrum of degenerative conditions. Restoration likely involves bolstering matrix stiffness to reduce the potential for astrocyte reactivity and local inflammation as well as repairing inhibitory binding sites for immune-signaling ligands. Facilitating repair rather than endogenous replacement of collagen degraded by disease or injury may represent the next frontier in developing therapies based on protection, repair, and regeneration of neurons in the central nervous system.

中文翻译：

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中枢神经系统中的胶原蛋白：对神经退行性变的贡献以及作为治疗靶点的前景

细胞外基质是一种富含生物活性的底物组合物，可提供生物物理稳定性，促进细胞间信号传导，并反映和控制局部微环境的生理状态。中枢神经系统 (CNS) 中的基质远非简单的机械支撑的惰性支架，而是在体内平衡中发挥积极作用，并提供广泛的适应和重塑能力以应对压力，否则将挑战神经元、神经胶质、和血管成分。主要成分是胶原蛋白，其特征性的三螺旋结构提供机械和生化稳定性，从而实现基质和驻留细胞之间的双向串扰。胶原蛋白超家族的多个成员对于大脑中的神经元成熟和回路形成、轴突引导和突触发生至关重要。在成熟组织中，胶原蛋白与其他纤维蛋白和糖蛋白相互作用，以维持三维介质，复杂的细胞网络可以通过该介质进行通信。虽然中枢神经系统中的胶原蛋白对于基质支架至关重要，但它也是高度动态的，具有多个与基质蛋白、细胞表面受体和其他配体结合的结合位点。这些相互作用正在成为中枢神经系统疾病和损伤的关键介质，特别是在基质硬度、星形胶质细胞募集和反应性以及局部微环境中促炎信号传导方面的变化。胶原蛋白结构和/或沉积的变化会影响大脑中的细胞信号传导和组织生物力学，进而改变细胞反应，包括抗原性、血管生成、神经胶质增生和免疫相关细胞的招募。这些因素均涉及基质胶原，导致中枢神经系统组织的再生能力有限。尝试使用肽片段重建基质的新兴疗法，包括富含胶原蛋白的支架和模拟物，在促进神经修复和再生方面具有巨大的潜力。我们小组和其他人的最新证据表明，用模拟肽修复蛋白酶降解的胶原蛋白螺旋有助于恢复中枢神经系统组织并促进神经元在广泛的退行性疾病中存活。恢复可能涉及增强基质硬度以降低星形胶质细胞反应性和局部炎症的可能性，以及修复免疫信号配体的抑制性结合位点。促进因疾病或损伤而降解的胶原蛋白的修复而不是内源性替代可能代表开发基于中枢神经系统神经元的保护、修复和再生的疗法的下一个前沿。