Lipid regulation and metabolism in myelin repair

目前用于治疗多发性硬化症的所有疗法都是针对免疫系统的抗炎药物，目前还没有批准的药物可以促进脱髓鞘病变的修复，而脱髓鞘病变是神经系统残疾的潜在原因。我们的长期目标是确定中枢神经系统脂质是如何受到脑激素变化的调节的，以及这是如何影响神经系统疾病的。该应用程序的总体目标是确定在脱髓鞘和再脱髓鞘过程中重要的脂质相关基因，并确定脂质组在脱髓鞘和再脱髓鞘过程中如何变化，这是实现我们长期目标的第一步。我们的中心假设是激素通过参与脂质代谢的基因转录调控促进髓鞘形成，而脂质调控对髓鞘再生的成功至关重要。我们的假设是基于研究表明，甲状腺激素调节大脑和少突胶质祖细胞（OPC）分化过程中的脂质相关基因，这是髓鞘形成的重要步骤。此外，包括固醇和溶血磷脂酸在内的几种脂类也与髓鞘再生有关。支持这项研究的基本原理是，它将为开发促进髓磷脂修复的新疗法确定脂质途径。中心假设将通过以下两个具体目标进行评估：(1)确定由核受体调节的脂质相关基因，并确定OPC分化所需的基因；(2)绘制髓鞘再生过程中髓磷脂脂质的变化。在第一个目标中，OPC分化试验将用于评估一组与髓鞘形成有关的核受体配体。然后进行rna测序以鉴定参与OPC分化和膜过程延伸的脂质相关基因。对于第二个目标，将从基于Plp-CreERT的诱导条件敲除小鼠脱髓鞘模型中分离脑脂质；Myrffl / fl应变。质谱分析将用于描述疾病过程中脱髓鞘和再脱髓鞘阶段的脑脂质组学变化。在申请人看来，拟议的研究是创新的，因为正在使用两种正交的方法来协同识别在髓鞘再生中重要的新脂质途径。本研究完成后，预计将发现一种或多种参与中枢神经系统髓鞘再生的脂质途径。这一贡献预计是重要的，因为它将增加对脱髓鞘再生过程中脂质如何调节的认识，并可能揭示脱髓鞘影响疾病治疗干预的新靶点。这些研究也将为将来有竞争力的R01拨款申请提供必要的初步数据。

All of the current therapies available for treating multiple sclerosis are anti-infllammatory agents that target the immune system, and there are no approved drugs that promote repair of demyelinated lesions, which is the underlying cause of neurological disability. Our long-term goal is to define how CNS lipids are regulated by changes in brain hormones and how this affects neurological disease. The overall objective in this application, which is the first step toward achieving our long-term goal, is to identify lipid-related genes that are important during remyelination and define how the lipidome changes during demyelination and remyelination. Our central hypothesis is that hormones promote myelination through transcriptional regulation of genes involved in lipid metabolism, and that regulation of lipids is critical for successful remyelination. Our hypotheses have been formulated based on studies showing that thyroid hormone regulates lipid-related genes in the brain and during oligodendrocyte progenitor cell (OPC) differentiation, which is an important step in myelination. In addition, several lipid classes including sterols and lysophosphatidic acids have been implicated in remyelination. The rationale that supports the proposed research is that it will identify lipid pathways for the development of new therapies for promoting myelin repair. The central hypothesis will be evaluated with the two following specific aims: (1) Identify lipid-related genes regulated by nuclear receptors and required for OPC differentiation; and (2) Map myelin lipid changes during remyelination. In the first aim, an OPC differentiation assay will be used to evaluate a panel of nuclear receptor ligands that have been implicated in myelination. RNA-sequencing will then be performed to identify lipid-related genes involved in OPC differentiation and membrane process extension. For the second aim, brain lipids will be isolated from an inducible conditional knockout mouse model of demyelination based on the Plp-CreERT;Myrffl/fl strain. Mass spectrometry analysis will be performed to profile the brain lipidomic changes in demyelinating and remyelinating phases of the disease course. The proposed research is innovative, in the applicant’s opinion, because two orthogonal approaches are being used to synergistically identify new lipid pathways of importance in remyelination. Upon completion of this proposed research, it is expected that one or more lipid pathways involved in CNS remyelination will be identified. This contribution is expected to be significant, because it will increase knowledge about how lipids are regulated during remyelination and may reveal a novel target for therapeutic intervention in diseases affected by demyelination. These studies will also provide necessary preliminary data for a competitive R01 grant application in the future.