Mechanisms in CNS myelination: Role of PD-lalpha/ATX

项目摘要 多发性硬化症（MS）是人类主要的脱髓鞘疾病， 这被认为主要是由于慢性脱髓鞘的退化，因此更脆弱的轴突。 因此，髓鞘再生代表了恢复MS神经功能的关键治疗目标。 目前，没有可利用的实际方法，其导致髓磷脂在体内的再生， 人脑鉴定这种治疗性再生促进方法的一个困难在于， 目前，关于调控细胞沿着分化的分子机制的知识仍然有限， 中枢神经系统（CNS）的髓鞘形成细胞谱系，即少突胶质细胞（OLG）。 有趣的是，已经发现具有分化成成熟OLG的能力的祖细胞存在于细胞内。 MS CNS。然而，由于目前尚未完全了解的原因，它们未能成熟。因此 有希望的治疗和髓鞘恢复疗法的方法在于表征分子生物学特性。 信号传导轴，可以促进发育OLG分化，但在MS CNS内被错误调节。在 在这方面，我们最近的研究确定了糖蛋白自分泌运动因子（ATX），也称为ENPP 2，PD-Iα/ATX或 lysoPLD，作为一种位于细胞外的因子，可以在发育过程中刺激OLG分化。在MS中， 另一方面，已经发现在CNS实质内ATXmRNA和蛋白水平降低。在 此外，我们最近的数据已经确定了ATX的酶促溶血磷脂酶D（lysoPLD）活性，已知 产生脂质信号分子溶血磷脂酸（LPA），作为ATX在 OLG谱系的早期阶段。重要的是，我们最近的数据表明ATX的lysoPLD活性发挥其 通过刺激组蛋白去乙酰化的作用，这是一种已被充分证明的表观遗传机制， 对于OLG的差异化至关重要。值得注意的是，组蛋白去乙酰化的减少已经发生了变化。 因此，ATX-LPA轴代表了一种可能的神经损伤。 一个有吸引力的候选信号轴，可以促进发展OLG分化，但 在MS CNS内失调。对于目前的建议，我们设计了一套研究，旨在 建立ATX-LPA轴作为OLG分化以及CNS髓鞘再生的关键调节因子。更 特别是我们的研究建立在ATX-LPA信号轴调节OLG的中心假设下 通过组蛋白脱乙酰化以及LPA受体信号传导经由表观遗传调节分化，以及 这种ATX介导的机制的缺陷导致髓鞘的修复效率低下。在漫长的- 长期而言，拟议的研究预计将导致功能活性的开发和测试， 靶向ATX-LPA轴并可能具有刺激CNS髓鞘的治疗潜力的化合物 在病理条件下再生，如在MS中所见。

PROJECT SUMMARY Permanent neurologic disability in the major demyelinating disease in human, Multiple Sclerosis (MS), is thought to be primarily due to the degeneration of chronically demyelinated and hence more vulnerable axons. Thus, remyelination represents a critical therapeutic objective for restoring neurologic function in MS. However, there are, at present, no practical approaches available that lead to the regeneration of myelin in vivo in the human brain. One difficulty in identifying such therapeutic regeneration-promoting approaches lies in the currently still limited knowledge about the molecular mechanisms that regulate the differentiation along the lineage of the myelinating cells of the central nervous system (CNS), namely oligodendrocytes (OLGs). Interestingly, progenitors with the capacity to differentiate into mature OLGs have been found present within the MS CNS. However, they fail to mature for reasons that are currently not fully understood. Thus, a promising approach toward a curative and myelin restoring therapy lies in the characterization of molecular signaling axes that can promote developmental OLG differentiation but are misregulated within the MS CNS. In this regard, our recent studies identified the glycoprotein autotaxin (ATX), also known as ENPP2, PD-Iα/ATX or lysoPLD, as an extracellularly located factor that can stimulate OLG differentiation during development. In MS, on the other hand, ATX mRNA and protein levels have been found reduced within the CNS parenchyma. In addition, our recent data have identified ATX's enzymatic lysophospholipase D (lysoPLD) activity, known to generate the lipid signaling molecule lysophosphatidic acid (LPA), as the mediator of ATX's functions on the early stages of the OLG lineage. Importantly, our recent data showed that ATX's lysoPLD activity exerts its effects via the stimulation of histone deacetylation, an epigenetic mechanism that has been well-demonstrated to be crucial for OLG differentiation. Notably, a shift toward a decrease in histone deacetylation has been implicated in contributing to the limitations in myelin repair seen in MS. Thus, the ATX-LPA axis represents an attractive candidate for a signaling axis that can promote developmental OLG differentiation but is misregulated within the MS CNS. For the present proposal we designed a set of studies that are aimed at establishing the ATX-LPA axis as a crucial regulator of OLG differentiation as well as CNS remyelination. More specifically our studies are set under the central hypothesis that the ATX-LPA signaling axis regulates OLG differentiation via epigenetic modulation through histone deacetylation as well as LPA receptor signaling, and that deficiency in this ATX-mediated mechanism leads to inefficient repair of the myelin sheath. In the long- term, the proposed studies are anticipated to lead to the development and testing of functionally active compounds that target the ATX-LPA axis and may have therapeutic potential for stimulating CNS myelin regeneration under pathologic conditions as they are seen in MS.