Lipid regulation and metabolism in myelin repair

髓磷脂修复中的脂质调节和代谢

• 批准号: 10434463
• 负责人: Meredith D Hartley
• 金额: $ 21.68万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-03 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434463
• 关键词: Affect; Applications Grants; Biological Assay; Brain; Cell Differentiation process; Cell membrane; Data; Demyelinations; Development; Disease; Disease Pathway; Future; Gene Expression Regulation; Genes; Goals; Hormones; Immune system; Knowledge; Lesion; Ligands; Lipids; Maps; Mass Spectrum Analysis; Metabolism; Molecular Analysis; Multiple Sclerosis; Myelin; Neurologic; Nuclear Receptors; Pathway interactions; Pharmaceutical Preparations; Phase; Process; Regulation; Research; Sterols; Therapeutic Intervention; Thyroid Hormones; Transcriptional Regulation; base; conditional knockout; disability; innovation; lipid metabolism; lipidome; lipidomics; lysophosphatidic acid; mouse model; myelination; nervous system disorder; new therapeutic target; novel therapeutics; oligodendrocyte progenitor; remyelination; repaired; targeted agent; transcriptome sequencing

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.

目前可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，并且没有批准的药物可以促进脱髓鞘病变的修复，这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质如何受到脑激素变化的调节，以及这如何影响神经系统疾病。本申请的总体目标是确定在髓鞘再生过程中重要的脂质相关基因，并确定脂质组在脱髓鞘和髓鞘再生过程中如何变化，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的转录调节来促进髓鞘形成，并且脂质的调节对于成功的髓鞘再生至关重要。我们的假设是基于研究表明甲状腺激素调节脑中和少突胶质祖细胞（OPC）分化过程中的脂质相关基因，OPC分化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质类与髓鞘再生有关。支持这项研究的基本原理是，它将确定脂质途径，用于开发促进髓鞘修复的新疗法。中心假设将通过以下两个具体目标进行评估：（1）鉴定由核受体调节并为OPC分化所需的脂质相关基因;（2）绘制髓鞘再生过程中髓鞘脂质变化。在第一个目标中，将使用OPC分化测定来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。对于第二个目的，将从基于Plp-CreERT;Myrffl/fl品系的脱髓鞘的诱导型条件性敲除小鼠模型中分离脑脂质。将进行质谱分析，以描述病程脱髓鞘和髓鞘再生阶段的脑脂质组学变化。在申请人看来，所提出的研究是创新的，因为两种正交方法被用于协同识别在髓鞘再生中重要的新脂质途径。在完成这项拟议的研究后，预计将确定一个或多个参与CNS髓鞘再生的脂质途径。预计这一贡献将是重要的，因为它将增加有关脂质在髓鞘再生过程中如何调节的知识，并可能揭示一种新的靶点，用于治疗受脱髓鞘影响的疾病。这些研究还将为将来的竞争性R 01赠款申请提供必要的初步数据。