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: 6317590
• 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 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6317590
• 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：（由申请人提供）本项目的长期目标是 更好地理解决定中枢神经系统的分子机制 正常发育过程中系统髓鞘形成作为改善 病理性脱髓鞘/髓鞘发育障碍下髓鞘修复的策略 条件，如它们发生在遗传性脑白质营养不良。 自修复以来 在这种病理条件下的髓鞘仍然是有限的， 尚未被表征的分子机制可能会显着 有助于髓鞘形成 这些机制包括： 由来源于CNS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性， 少突胶质细胞来源的磷酸二酯酶-I/自分泌运动因子（PD-I α/ATX）是一种 目前尚未表征的分子过程的重要组成部分， 调节中枢神经系统髓鞘形成。 PD-I alpha/ATX由 分化的少突胶质细胞在发育时间点， 少突胶质细胞积极参与髓鞘的产生。 调查人员的初步数据表明，释放PD-I α/ATX受蛋白水解切割调节。 具体目标1 将研究调节可溶性， 少突胶质细胞衍生的PD-I α/ATX。 由于主序列 PD-I-alpha/ATX揭示了可能参与PD-I-alpha/ATX的结构域。 细胞-细胞和/或细胞-细胞外基质相互作用，潜在PD-1 将在研究中鉴定CNS的α/ATX相互作用分子 通过使用生物化学和分子生物学技术， 接近。 总之，这些研究将提供新的见解， 发育期间控制CNS髓鞘形成的PD-I α/ATX介导事件 并且可以刺激脱髓鞘/髓鞘形成障碍疾病中的髓鞘再生。