Molecular regulation of myelin development and repair by Ick kinase

少突胶质细胞是髓鞘形成的大胶质细胞，存在于中枢神经系统的所有区域。 神经系统髓鞘的主要功能是确保快速和 电子信号的可靠传输。在发育过程中， 前体细胞（OPCs）必须经历一系列的形态和分子生物学过程， 在它们完全分化成成熟的髓鞘形成细胞之前， 少突胶质细胞少突胶质细胞的分化和髓鞘形成过程 受到蛋白质酪氨酸磷酸化的调节。最近我们发现， 细胞质丝氨酸/苏氨酸激酶在分化中选择性上调， OPCs和Ick的破坏导致OL分化的显著抑制。在 在本申请中，我们假设Ick增强OPC分化和轴突生长， 在发育过程中通过Ick形成髓鞘，并在发育后增强髓鞘修复 脱髓鞘损伤。本申请的第一个目的是检查Ick是否 表达是Ick条件突变小鼠中髓鞘发育所需的， 在OPCs中诱导表达Ick蛋白促进发育性髓鞘形成 诱导型转基因小鼠在第二个目标中，我们将检验Ick 表达也是成年动物中轴突髓鞘再生所必需的， 诱导型转基因小鼠中Ick的过表达可促进髓鞘的恢复 脱髓鞘后 这项研究可以帮助我们了解分子机制， 控制轴突髓鞘形成过程，并提供深入了解的发展， 刺激少突胶质细胞再生和髓鞘再生的分子方法 脱髓鞘疾病

Oligodendrocytes are myelin-forming macroglia found in all regions of the central nervous system. The major function of myelin sheaths is to ensure the rapid and faithful transmission of electrical signals. During development, oligodendrocytes precursor cells (OPCs) have to go through a series of morphological and molecular changes before they become fully differentiated into mature myelinating oligodendrocytes. The differentiation and myelination processes of oligodendrocytes are regulated by protein tyrosine phosphorylation. Recently we found that Ick cytoplasmic serine/threonine kinase is selectively up-regulated in differentiating OPCs and disruption of Ick resulted a significant inhibition of OL differentiation. In this application, we hypothesize that Ick enhances OPC differentiation and axonal myelination by Ick during development and enhance myelin repair following demyelination insults. The first aim of this application is to examine whether Ick expression is required for myelin development in Ick conditional mutant mice, and induced expression of Ick protein in OPCs promotes developmental myelination in inducible transgenic mice. In the second aim, we will test the hypothesis that Ick expression is also required for axonal remyelination in adult animals and overexpression of Ick in inducible transgenic mice can promote myelin recovery following demyelination This line of study could help us understand molecular mechanisms that control axonal myelination process and provide insights into the development of molecular approaches to stimulate oligodendrocyte regeneration and remyelination in demyelinating diseases.