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.

与健康相关：超过40万美国人患有多发性硬化症， 严重残疾最终影响到大约85%的多发性硬化症人口。残疾 多发性硬化的主要原因是脱髓鞘和轴突损伤。轴突损伤本身与 脱髓鞘作为重要的轴突横断发生在急性脱髓鞘病变中， 而渐进性轴突丢失与慢性脱髓鞘有关。防止脱髓鞘 和增强髓鞘再生对于保持中枢神经系统的完整性和促进 我们认为TLR2-MyD88通路在MS的康复过程中起中心作用。 多发性硬化症的脱髓鞘过程和重新髓鞘形成失败我们的假设是 先天免疫细胞中TLR2-MyD88通路的激活导致炎症 破坏少突胶质细胞、髓鞘和轴突，而激活它们 少突胶质细胞中的途径阻止其正常成熟，从而阻止 重新髓鞘形成。 长期目标：我们的长期目标是定义多发性硬化症的分子途径，即 在损伤和修复过程中发挥重要作用，用作治疗靶点。在这 我们的目标是确定TLR2-MyD88通路在 导致脱髓鞘和轴突损伤，并抑制再髓鞘形成，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 脱髓鞘、少突胶质细胞在MS模型系统中的TLR2-MyD88通路 死亡、轴突损伤、神经元死亡、少突胶质细胞成熟和再髓鞘形成 终点。目的1利用铜试剂介导的脱髓鞘作用研究 TLR2-MyDBB途径在脱髓鞘过程中的作用 对这个过程的先天免疫力。相关的基因敲除小鼠用于建立 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。 在目标2中，我们将研究TLR2-MyD88通路对再髓鞘形成的影响 铜试剂和溶血磷脂模型。重新髓鞘形成的定量评估， 少突胶质细胞成熟、少突胶质细胞存活、神经元存活和轴突 我们会做到正直的。