CNS myelination--role of phosphodiesterase-I/autotaxin

中枢神经系统髓鞘形成——磷酸二酯酶-I/自分泌运动因子的作用

• 批准号: 6536310
• 负责人: BABETTE FUSS
• 金额: $ 7.25万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6536310
• 关键词: cell line; central nervous system; developmental neurobiology; enzyme activity; enzyme induction /repression; enzyme mechanism; glycoproteins; immunoprecipitation; infant animal; intermolecular interaction; laboratory rat; leukodystrophy; mass spectrometry; membrane proteins; metalloendopeptidases; molecular biology; molecular site; myelination; oligodendroglia; phosphodiesterases; protein structure function; tissue /cell culture; transfection; western blottings; yeast two hybrid system

DESCRIPTION: (provided by applicant) The long-term goal of this project is to better understand the molecular mechanisms that determine central nervous system myelination during normal development as an approach to improve strategies for myelin repair under pathological, de-/dysmyelinating conditions, such as they occur in hereditary leukodystrophies. Since repair of the myelin sheath under such pathological conditions still remains limited, yet to be characterized molecular mechanisms are likely to significantly contribute to proper myelination. These mechanisms include those that are mediated by proteins derived from the myelin forming cells of the CNS, oligodendrocytes. The central hypothesis for the proposed studies is that soluble, oligodendrocyte-derived phosphodiesterase-I/autotaxin (PD-I alpha/ATX) is an essential component of a currently uncharacterized molecular process that regulates proper CNS myelination. PD-I alpha/ATX is released by differentiated oligodendrocytes at the developmental time-point at which oligodendrocytes are actively involved in the generation of the myelin sheath. The investigator's preliminary data indicate that the release of PD-I alpha/ATX is regulated by proteolytic cleavage. Accordingly, Specific Aim 1 will study the molecular mechanism that regulates the generation of soluble, oligodendrocyte-derived PD-I alpha/ATX. Since the primary sequence of PD-I-alpha/ATX reveals structural domains that are likely to be involved in cell-cell and/or cell-extracellular matrix interactions, potential PD-I alpha/ATX-interacting molecules of the CNS will be identified in the studies of Specific Aim 2 by using biochemical as well as molecular biological approaches. Taken together, these studies will provide novel insights into PD-I alpha/ATX-mediated events that control CNS myelination during development and that may stimulate remyelination in de-/dysmyelinating diseases.

描述：(申请者提供)这个项目的长期目标是更好地理解决定中枢神经的分子机制 系统在正常发育过程中的髓鞘形成是一种改善的方法 病理性脱髓鞘/髓鞘损伤下髓鞘修复的策略 遗传性脑白质营养不良等病症。自修以来 在这样的病理条件下，髓鞘的数量仍然有限， 尚待确定的分子机制可能会显著 有助于适当的髓鞘形成。这些机制包括 由来自中枢神经系统髓鞘形成细胞的蛋白质介导， 少突胶质细胞。 拟议研究的中心假设是，可溶的， 少突胶质细胞来源的磷酸二酯酶-I/自体趋化蛋白(PD-Iα/ATX)是一种 一种目前尚未确定的分子过程的基本组成部分 调节适当的中枢神经系统髓鞘形成。PD-Iα/ATX由 在发育时间点分化的少突胶质细胞 少突胶质细胞积极参与髓鞘的形成。 调查人员的初步数据表明，Pd-I的释放 Alpha/ATX受蛋白水解性切割调控。因此，具体目标1 将研究调节可溶性物质产生的分子机制， 少突胶质细胞来源的PD-Iα/ATX。因为主序列是 PD-I-α/ATX揭示了可能参与的结构域 细胞-细胞和/或细胞-细胞外基质相互作用，潜在的PD-I 将在研究中确定中枢神经系统的Alpha/ATX相互作用分子 通过使用生化和分子生物学来实现特定的目的2 接近了。综上所述，这些研究将为 PD-Iα/ATX介导的在发育过程中控制中枢神经系统髓鞘形成的事件 这可能会刺激脱髓鞘/髓鞘障碍疾病的重新髓鞘形成。