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Molecular regulation of myelin development and repair by Ick kinase

Ick 激酶对髓磷脂发育和修复的分子调节

基本信息

批准号：
9237980
负责人：
Mengsheng Qiu
金额：
$ 23.1万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9237980
关键词：
Address Animal Model Axon Birth Cell Communication Cell Differentiation process Cells Cuprizone Demyelinating Diseases Demyelinations Development Developmental Process Ensure In Situ Injury Intestines Knock-out Knockout Mice Knowledge Ligands Molecular Mus Myelin Myelin Sheath Natural regeneration Nature Neuraxis Neurologic Oligodendroglia Patients Pattern Phenotype Phosphorylation Phosphotransferases Play Process Protein Kinase Protein-Serine-Threonine Kinases Proteins Recovery Regulation Role SHH gene Series Signal Transduction Spinal Cord Spinal cord injury patients Surface Testing Time Transducers Transgenic Mice Tyrosine Phosphorylation axon regeneration base conditional mutant insight macroglia mature animal mutant myelination neonatal death oligodendrocyte precursor overexpression postnatal precursor cell receptor remyelination repaired screening smoothened signaling pathway transmission process

项目摘要

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.

少突胶质细胞是髓鞘形成的大胶质细胞，见于大脑中央的所有区域。神经系统。髓鞘的主要功能是确保快速和电信号的忠实传输。在发育过程中，少突胶质细胞前体细胞必须经过一系列的形态和分子生物学过程。在它们完全分化为成熟髓鞘之前的变化少突胶质细胞。少突胶质细胞的分化和髓鞘形成过程是由蛋白质酪氨酸磷酸化调节的。最近我们发现Ick 胞浆丝氨酸/苏氨酸激酶在分化过程中选择性上调 OPC和Ick的破坏导致了OL分化的显著抑制。在……里面在这一应用中，我们假设Ick促进OPC分化和轴突 Ick在发育过程中的髓鞘形成和增强随后的髓鞘修复脱髓鞘侮辱。这个应用程序的第一个目标是检查Ick 在Ick条件突变小鼠中，髓鞘发育需要表达，并且在OPC中诱导表达Ick蛋白促进小鼠发育髓鞘形成可诱导的转基因小鼠。在第二个目标中，我们将检验Ick的假设成年动物的轴突重新髓鞘形成也需要表达诱导转基因小鼠过表达Ick可促进髓鞘恢复脱髓鞘后这一系列研究可以帮助我们理解控制轴突髓鞘形成过程并提供对小鼠少突胶质细胞再生和再髓鞘形成的分子机制脱髓鞘疾病。