Inhibition of myelin regeneration by tenascin proteins and the associated matrisom

有序的轴突连接产生神经网络，这些网络在神经解剖系统中被组织起来。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(CNS)正常运作的先决条件。除了连接的架构之外，正常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，大多数大的轴突被髓鞘包裹，髓鞘是由专门的细胞-成熟的少突胶质细胞-产生的。髓鞘是动作电位跳跃传导的基础，保证了信息的快速传递。此外，它还提供代谢支持，有助于维持轴突的完整性。在髓鞘形成过程中，髓鞘膜以螺旋的方式包裹在轴突周围，形成多层致密的髓鞘。少突胶质细胞代表中枢神经系统的一个独立的神经胶质谱系。它们起源于神经发育过程中的主要神经干细胞和神经胶质前体细胞(NSPC)室--放射状胶质细胞。胶质发生始于少突胶质前体细胞(OPC)的规范，这些细胞出生在发育中的神经管的不同区域。在尾侧，它们在靠近中线的形态因子的影响下出现在腹侧神经管中。长期以来，髓鞘一直被认为是一种相当惰性的结构，但同时也清楚地表明，在人类出生后的发育、各种生理过程和衰老的背景下，髓鞘是不断重组的。此外，重新组织髓鞘的能力也反映了髓鞘本质上是一个再生系统。这在病变的背景下是有意义的，因为中枢神经系统的各种疾病状况涉及髓鞘的破坏，从而导致功能损害。众所周知，成熟的少突胶质细胞不会再生髓鞘缺陷。因此，生长在中枢神经系统的少突胶质前体细胞(OPC)有修复髓鞘缺失的任务。然而，外在因素阻碍了成年中枢神经系统的再生过程。该实验室已经确定了中枢神经系统细胞外基质(ECM)的成分，这是一个被称为母体的复杂分子系统的一部分。在他们的初步工作中，实验室已经证明了不同的tenascin蛋白和相关的神经矩阵体交联体在CNS病变中上调，并以不同的方式干扰OPC的分化。在目前的建议中，我们建议研究母体依赖抑制重新髓鞘形成的细胞和分子基础。其目的是了解基于母体的髓鞘再生抑制物，以寻找促进髓鞘重塑和髓鞘相关疾病过程中功能恢复的方法。

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.