Lipid regulation and metabolism in myelin repair

髓磷脂修复中的脂质调节和代谢

• 批准号: 10242613
• 负责人: Meredith D Hartley
• 金额: $ 13.9万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242613
• 关键词: Address; Adult; Affect; Age; Agonist; Applications Grants; Area; Biological Assay; Biological Markers; Brain; Cell Death; Cell Differentiation process; Cell membrane; Cells; Cholesterol Homeostasis; Corpus Callosum; Cuprizone; Data; Demyelinations; Development; Disease; Disease Pathway; Enterobacteria phage P1 Cre recombinase; Family; Fatty Acids; Future; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Goals; Hormones; Hour; Human; Immune system; Incubated; Knowledge; Laboratories; Laboratory Study; Lecithin; Lesion; Ligands; Lipids; Maps; Mass Spectrum Analysis; Measures; Mediator of activation protein; Metabolism; Modeling; Molecular Analysis; Motor; Multiple Sclerosis; Mus; Myelin; Neurologic; Nuclear Hormone Receptors; Nuclear Receptors; Oleic Acids; Oligodendroglia; Outcome; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Play; Population; Process; Publishing; Recovery; Regulation; Research; Resolution; Role; Rotarod Performance Test; Spinal Cord; Stains; Sterols; Symptoms; Tachycardia; Tamoxifen; Technology; Therapeutic Intervention; Thyroid Hormone Receptor; Thyroid Hormones; Tissue Sample; Toxin; Transcriptional Regulation; Triglyceride Metabolism; base; brain tissue; conditional knockout; disability; drug candidate; experimental study; high throughput screening; imaging approach; innovation; interest; lipid metabolism; lysophosphatidic acid; motor disorder; motor recovery; mouse model; myelination; nervous system disorder; new therapeutic target; novel therapeutics; oligodendrocyte progenitor; receptor; remyelination; repaired; side effect; stem cells; targeted agent; transcriptome sequencing; transcriptomics; white matter

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靶向治疗多发性硬化症的抗炎剂。 免疫系统，也没有批准的药物，促进修复脱髓鞘病变，这是 神经系统残疾的根本原因我们的长期目标是确定中枢神经系统脂质是如何调节的 大脑激素的变化以及它如何影响神经系统疾病。在这方面的总体目标 应用，这是实现我们长期目标的第一步，是确定与脂质相关的基因， 在髓鞘再生过程中是重要的，并定义了脱髓鞘过程中脂质组的变化， 髓鞘再生我们的中心假设是激素通过转录促进髓鞘形成 调节参与脂质代谢的基因，并且脂质的调节对于成功的 髓鞘再生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）分化期间的脂质相关基因， 这是髓鞘形成的重要步骤。此外，包括甾醇和 溶血磷脂酸与髓鞘再生有关。支持建议的理由 研究表明，它将确定脂质途径，以开发促进髓鞘修复的新疗法。 本研究将从以下两个方面对中心假设进行评估：（1）确定与血脂相关的基因 由核受体调节并为OPC分化所需;和（2）映射在OPC分化期间的髓鞘脂质变化。 髓鞘再生在第一个目标中，将使用OPC分化测定来评估一组核细胞， 与髓鞘形成有关的受体配体。然后进行RNA测序，以确定 脂质相关基因参与OPC分化和膜突延伸。对于第二个目标， 脑脂质将从脱髓鞘的诱导性条件敲除小鼠模型中分离， Plp-CreERT;Myrffl/fl菌株。将进行质谱分析以分析脑脂质组学特征。 疾病过程中脱髓鞘和髓鞘再生阶段的变化。拟议的研究是 在申请人看来，这是创新的，因为两种正交方法被用于协同地 识别在髓鞘再生中重要的新脂质途径。在完成这项拟议研究后， 预期将鉴定出参与CNS髓鞘再生的一种或多种脂质途径。这一贡献 预计将是重要的，因为它将增加有关如何调节脂质的知识， 髓鞘再生，并可能揭示一个新的目标，为治疗干预疾病的影响， 脱髓鞘这些研究还将为竞争性R 01赠款提供必要的初步数据 在未来的应用。