Inhibition of myelin regeneration by tenascin proteins and the associated matrisom

腱蛋白和相关基质体对髓磷脂再生的抑制

• 批准号: 407698736
• 负责人: Professor Dr. Andreas Faissner
• 金额: --
• 依托单位: Lehrstuhl für Zellmorphologie und Molekulare Neurobiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/407698736?language=en
• 关键词: Inhibition; myelin; regeneration; tenascin; proteins

The ordered axonal connections generate neuronal networks that are organized in neuroanatomical systems. Integrity of these networks and undisturbed information transfer at synapses are prerequisites for the correct functioning of the central nervous system (CNS). Beyond the architecture of connectivity, adequate functioning also requires rapid information transfer by axonal connections. In the mammalian CNS, most of the large axons are enwrapped by myelin sheaths that are produced by specialized cells, the mature oligodendrocytes. The myelin sheath underlies the saltatory conduction of action potentials and secures fast information transmission. Furthermore, it provides metabolic support and contributes to the maintenance of axonal integrity. During the process of myelination, myelin membranes wrap around axons in a spiral manner, resulting in a multilamellar compacted myelin sheath. Oligodendrocytes represent an independent glial lineage of the CNS. They arise from radial glia cells, the principal neural stem and glial progenitor cell (NSPC) compartment during neural development. Gliogenesis begins with the specification of oligodendrocyte precursor cells (OPCs) that are born in distinct regions of the developing neural tube. In the caudal region, they emerge in the ventral neural tube under the influence of morphogens, close to the midline. For a long time period, myelin has been considered a rather inert structure, but meanwhile it is clear that the myelin sheath is continuously reorganized in the human in the context of postnatal development, various physiological processes and aging. Furthermore, the ability of reorganizing the myelin sheath also reflects that myelin is an essentially regenerating system. This is of interest in the context of lesion because various disease conditions of the CNS involve a destruction of the myelin sheaths, with resulting functional impairments. It is known that mature oligodendrocytes do not regenerate myelin defects. Hence, the oligodendrocyte precursor cells (OPCs) that populate the CNS have the task to repair myelin deficits. However, extrinsic factors hinder the regeneration process in the adult CNS. The laboratory has characterized constituents of the extracellular matrix (ECM) of the CNS, which is part of a complex molecular system known as the matrisome. In their preliminary work the laboratory has shown that distinct tenascin proteins and the associated interactome of the neural matrisome are upregulated in CNS lesions and interfere in distinct ways with the differentiation of OPCs. In the present proposal, we suggest to study cellular and molecular bases of the matrisome-dependent inhibition of remyelination. The aim is to understand the matrisome-based inhibitors of myelin regeneration in order to find ways to promote the reformation of myelin and the restitution of function in myelin associated disease processes.

有序的轴突连接产生了在神经解剖系统中组织起来的神经网络。这些网络的完整性和突触间不受干扰的信息传递是中枢神经系统正常运作的先决条件。除了连接的架构，足够的功能还需要通过轴突连接快速传递信息。在哺乳动物的中枢神经系统中，大多数大轴突被髓鞘包裹，髓鞘是由成熟的少突胶质细胞产生的。髓鞘是动作电位跳跃式传导的基础，确保信息的快速传递。此外，它还提供代谢支持并有助于维持轴突的完整性。在髓鞘形成过程中，髓鞘膜以螺旋状缠绕在轴突周围，形成多层致密的髓鞘。少突胶质细胞代表了中枢神经系统的一个独立的胶质谱系。它们起源于神经发育过程中的放射状胶质细胞，主要神经干和胶质祖细胞（NSPC）室。神经胶质瘤的形成始于少突胶质细胞前体细胞（OPCs）的形成，这些细胞产生于发育中的神经管的不同区域。在尾侧区域，它们在形态因子的影响下出现在靠近中线的腹侧神经管中。长期以来，髓磷脂一直被认为是一种相当惰性的结构，但与此同时，髓磷脂鞘在人类出生后的发育、各种生理过程和衰老过程中不断被重组。此外，重组髓鞘的能力也反映了髓鞘本质上是一个再生系统。这在病变的背景下很有趣，因为中枢神经系统的各种疾病都涉及髓鞘的破坏，导致功能损伤。众所周知，成熟的少突胶质细胞不能再生髓磷脂缺陷。因此，填充中枢神经系统的少突胶质前体细胞（OPCs）具有修复髓磷脂缺陷的任务。然而，外部因素阻碍了成人中枢神经系统的再生过程。该实验室对中枢神经系统的细胞外基质（ECM）的成分进行了表征，该成分是称为基质体的复杂分子系统的一部分。在他们的初步工作中，实验室已经表明，在中枢神经系统病变中，不同的tenascin蛋白和神经基质的相关相互作用组上调，并以不同的方式干扰OPCs的分化。在本提案中，我们建议研究基质依赖性抑制髓鞘再生的细胞和分子基础。目的是了解基于基质体的髓鞘再生抑制剂，以便找到促进髓鞘改革和髓鞘相关疾病过程中功能恢复的方法。