Functional Link Between Innate Immunity, Oligodendrocyte Development, and Myelina

先天免疫、少突胶质细胞发育和髓鞘之间的功能联系

• 批准号: 7698962
• 负责人: TIMOTHY VARTANIAN
• 金额: $ 29.58万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7698962
• 关键词: Acute; Affect; Agonist; American; Amyloid beta-Protein Precursor; Animal Model; Animals; Axon; Biological Models; Brain; Cells; Cessation of life; Chronic; Corpus Callosum; Cuprizone; Data; Demyelinations; Development; Diet; Electron Microscopy; Event; Extracellular Matrix; Failure; Future; Genetic; Goals; Grant; Health; Histologic; Hyaluronan; Immune; Immunofluorescence Immunologic; In Vitro; Inflammation; Inflammatory; Injury; Knockout Mice; Lead; Lesion; Link; Luxol Fast Blue MBS; Lysophosphatidylcholines; Mediating; Microglia; Modeling; Molecular; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; NF-kappa B; Natural Immunity; Natural regeneration; Neuraxis; Neuronal Injury; Neurons; Oligodendroglia; Pathway interactions; Phase; Play; Population; Process; Production; Publishing; Recovery; Research; Role; Secondary to; Signal Transduction; Staining method; Stains; Stem cells; TLR2 gene; Testing; Therapeutic; Tissues; Toll-Like Receptor 2; Toxin; chronic demyelination; cytokine; design; disability; disabling disease; feeding; functional loss; in vitro Model; in vivo; injury and repair; laser capture microdissection; loss of function; neuronal survival; neutralizing monoclonal antibodies; null mutation; pathogen; prevent; repaired; research study; therapeutic target

Health Relatedness: Over 400,000 Americans are afflicted with multiple sclerosis (MS), with severe disability ultimately affecting ~ 85% of the total MS population. Disability in MS is primarily due to demyelination and axonal injury. Axonal injury itself is tied to demyelination as significant axonal transection occurs in acute demyelinatng lesions, and gradual axonal loss is linked to chronic demyelination. Preventing demyelination and enhancing remyelination are essential to preserving CNS integrity and promoting recovery in MS. We propose that the TLR2-MyD88 pathway is central to both the process of demyelination and failure of remyelination in MS. Our hypothesis is that activation of the TLR2-MyD88 pathway in innate immune cells leads to inflammatory destruction of oligodendrocytes, myelin, and axons, whereas, activation of this same pathway in oligodendrocytes blocks their normal maturation thus preventing remyelination. Long-term goals: Our long-term goals are to define molecular pathways in MS, that play essential roles in the injury and repair process, for use as therapeutic targets. In this proposal our goal is to determine the importance of the TLR2-MyD88 pathway in causing demyelination and axonal injury, and in inhibiting remyelination, through in vivo and in vitro modeling. Research Approach: In each aim, the common goal is to determine the function of the TLR2-MyD88 pathway in MS model systems using demyelination, oligodendrocyte death, axonal injury, neuronal death, oligodendrocyte maturation and remyelination as end points. In aim 1 cuprizone mediated demyelination is used to study the impact of the TLR2-MyDBB pathway on the process of demyelination and the contribution in innate immunity to this process. Relevant knock-out mice are used to establish functional significance of TLR2 and MyD88. Quantitative assessments of demyelination, oligodendrocyte death, axonal injury, neuronal death, and inflammation will be made. In aim 2 we will study the impact of the TLR2-MyD88 pathway on remyelination using the cuprizone and lysolecithin models. Quantitative assessments of remyelination, oligodendrocyte maturation, oligodendrocyte survival, neuronal survival, and axonal integrity will be made.

健康相关性：超过40万美国人患有多发性硬化症（MS）， 严重的残疾最终影响约85％的MS总数。残疾 在MS中，主要是由于脱髓鞘和轴突损伤。轴突损伤本身与 脱髓鞘作为明显的轴突横向发生在急性脱髓鞘病变中， 逐渐的轴突损失与慢性脱髓鞘有关。防止脱髓鞘 增强延期性对于保持中枢神经系统的完整性和促进至关重要 MS恢复。我们建议TLR2-MYD88途径对于这两种途径都是核心 MS中脱髓鞘和雷髓的失败过程。我们的假设是 先天免疫细胞中TLR2-MYD88途径的激活导致炎症 少突胶质细胞，髓磷脂和轴突的破坏，而这种激活 少突胶质细胞中的途径阻止其正常成熟，从而阻止 再髓。 长期目标：我们的长期目标是定义MS中的分子途径， 在伤害和维修过程中起着重要的作用，以用作治疗目标。在这个 提案我们的目标是确定TLR2-Myd88途径的重要性 导致脱髓鞘和轴突损伤，并通过 体内和体外建模。 研究方法：在每个目标中，共同的目标是确定 MS模型系统中的TLR2-MYD88途径，使用脱髓鞘，少突胶质细胞 死亡，轴突损伤，神经元死亡，少突胶质细胞的成熟和透明度为 终点。在AIM 1 Cuprizone介导的脱髓鞘用于研究 TLR2-MYDBB途径在脱髓鞘过程中 对这一过程的先天免疫力。相关的淘汰小鼠用于建立 TLR2和MYD88的功能意义。脱髓鞘的定量评估， 将造成少突胶质细胞死亡，轴突损伤，神经元死亡和炎症。 在AIM 2中，我们将研究使用TLR2-MYD88途径对使用Remerelination的影响 Cuprizone和Lysolecithin模型。定量评估， 少突胶质细胞成熟，少突胶质细胞存活，神经元存活和轴突 将建立诚信。