Lipid regulation and metabolism in myelin repair

目前所有可用于治疗多发性硬化症的疗法都是针对免疫系统的抗炎药，目前还没有批准的药物来促进脱髓鞘病变的修复，脱髓鞘病变是神经功能障碍的根本原因。我们的长期目标是确定中枢神经系统脂类如何受到大脑激素变化的调节，以及这如何影响神经疾病。这项应用的总体目标是确定在再髓鞘形成过程中重要的脂质相关基因，并确定脂体在脱髓鞘和再髓鞘形成过程中的变化，这是实现我们长期目标的第一步。我们的中心假设是，激素通过转录调节参与脂代谢的基因来促进髓鞘形成，而脂类的调节对于成功的再髓鞘形成至关重要。我们的假设是基于研究表明，甲状腺激素调节大脑中和少突胶质前体细胞(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，包括甾醇和溶血磷脂酸在内的几种脂类与髓鞘再生有关。支持这项拟议研究的基本原理是，它将为促进髓鞘修复的新疗法的开发确定脂质途径。中心假说将以以下两个具体目标进行评估：(1)识别核受体调节的、OPC分化所需的脂质相关基因；(2)映射重新髓鞘形成过程中髓鞘脂质的变化。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，以确定与OPC分化和膜过程延长有关的脂质相关基因。对于第二个目的，将从基于PLP-CreERT；Myrffl/fl株的可诱导的条件性基因敲除的脱髓鞘小鼠模型中分离脑脂。将进行质谱分析，以描述疾病病程中脱髓鞘和重新髓鞘阶段的大脑脂体变化。申请人认为，这项拟议的研究是创新的，因为两种正交方法正在被用于协同识别在重新髓鞘形成中重要的新的脂质途径。在这项拟议的研究完成后，预计将确定参与中枢神经系统髓鞘再分化的一条或多条脂质途径。这一贡献预计将是重大的，因为它将增加对再髓鞘形成过程中脂类如何调节的了解，并可能揭示受脱髓鞘影响的疾病的治疗干预的新靶点。这些研究还将为未来竞争性R01赠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.