Cdk5 regulates oligodendrocyte development, myelination and repair

Cdk5 调节少突胶质细胞发育、髓鞘形成和修复

• 批准号: 8337843
• 负责人: ROBERT H. MILLER
• 金额: $ 34.34万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8337843
• 关键词: Adult; Affect; Animals; Area; Axon; Birth; Brain; CSPG4 gene; Cell Cycle; Cells; Complement; Cyclin-Dependent Kinase 5; Data; Defect; Demyelinating Diseases; Demyelinations; Development; Disease; Environment; Failure; Genetic; Goals; Histologic; Impairment; In Vitro; Individual; Inflammatory; Knockout Mice; Lesion; Mediating; Modeling; Molecular; Molecular Genetics; Monitor; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; Nervous System Physiology; Neurons; Oligodendroglia; Pathway interactions; Patients; Play; Progressive Disease; Psyche structure; RNA Interference; Recovery of Function; Regulation; Role; Shivering; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Slice; Spinal Cord; Staging; Structure of thyroid parafollicular cell; Tamoxifen; Technology; Testing; Therapeutic; United States; axonal degeneration; disability; in vivo; insight; myelination; neuron development; new therapeutic target; novel; novel strategies; novel therapeutics; oligodendrocyte lineage; oligodendrocyte precursor; overexpression; postnatal; precursor cell; prevent; relating to nervous system; remyelination; repaired; research study; response; therapeutic development

DESCRIPTION (provided by applicant): Oligodendrocyte precursors (OPCs) differentiate into oligodendrocytes that are the myelinating cells of the vertebrate CNS. Myelin sheaths wrap axons in the brain and spinal cord and maintain axonal function and promote rapid conduction of electrical impulses. Any damage to myelin sheaths, such as occurs in multiple sclerosis, results in loss of axonal conduction and ultimately axonal degeneration and irreversible neural disability leading to serious physical or mental impairments. Multiple sclerosis is a devastating disease that affects more than 300,000 individuals in the United States. Current therapies are directed towards regulating the inflammatory aspects of the disease, however long term functional recovery will depend upon successful myelin repair in the CNS. Recent studies suggest that many areas of demyelination in the brains of MS patients contain OPCs but the ability of these cells to repair damage is limited because they fail to differentiate for reasons tat are currently unknown. A detailed understanding of the mechanisms controlling OPC maturation and myelination will therefore provide new insights and novel therapeutic strategies for enhancing myelin repair in MS. The experiments described in this proposal will explore the roles of the intracellular signaling molecule cyclin dependent kinase 5 (Cdk5) and its co-activators p35/p39, in regulating the development of OPCs, myelination and remyelination. Cdk5 is known to be involved in various signaling pathways that are key for CNS development. Our preliminary data has revealed novel functions of Cdk5 in controlling the development of OPC and myelination. The proposed study will explore whether Cdk5 within cells of the oligodendrocyte lineage regulates their development and myelination in vitro and in vivo using molecular and genetic approaches. We will identify the roles p35/p39 play in mediating Cdk5 modulation of OPC maturation and myelination. To determine whether the Cdk5 pathway is a novel potential target for therapeutic development we will test whether Cdk5 is essential for remyelination in adult CNS after the induction of focal demyelinating lesions. To accomplish this we will selectively delete Cdk5 from OPCs in the adult CNS during demyelination. Successful completion of the proposed studies will provide critical insights into the signaling mechanisms regulating OPC maturation and myelination and provide novel targets to promote myelin repair.

描述(申请人提供)：少突胶质前体细胞(OPC)分化为少突胶质细胞，是脊椎动物中枢神经系统的髓鞘细胞。髓鞘包裹着大脑和脊髓中的轴突，维持轴突功能，促进电脉冲的快速传导。任何髓鞘损伤，如多发性硬化症，都会导致轴突传导丧失，最终导致轴突变性和不可逆转的神经功能障碍，导致严重的身体或精神障碍。多发性硬化症是一种毁灭性的疾病，在美国影响着30多万人。目前的治疗方向是调节疾病的炎症方面，然而长期的功能恢复将取决于中枢神经系统的髓鞘修复成功。最近的研究表明，MS患者大脑中许多脱髓鞘区域含有OPC，但这些细胞修复损伤的能力有限，因为它们无法分化，原因目前尚不清楚。因此，对控制OPC成熟和髓鞘形成的机制的详细了解将为促进MS的髓鞘修复提供新的见解和新的治疗策略。本文所描述的实验将探索细胞内信号分子细胞周期蛋白依赖性激酶5(CDK5)及其共激活因子p35/P39在调控OPC的发育、髓鞘形成和再髓鞘形成中的作用。已知CDK5参与了对中枢神经系统发育起关键作用的各种信号通路。我们的初步数据揭示了CDK5在控制OPC的发展和髓鞘形成方面的新功能。这项拟议的研究将利用分子和遗传方法探索少突胶质细胞谱系细胞内的CDK5是否调节其体外和体内的发育和髓鞘形成。我们将确定p35/p39在介导CDK5对OPC成熟和髓鞘形成的调节中所起的作用。为了确定CDK5通路是否是治疗发展的一个新的潜在靶点，我们将测试CDK5是否对诱导局灶性脱髓鞘损伤后成人中枢神经系统的重新髓鞘形成是必不可少的。为了实现这一点，我们将在脱髓鞘过程中选择性地从成人中枢神经系统的OPC中删除CDK5。这些研究的成功完成将为调控OPC成熟和髓鞘形成的信号机制提供关键的见解，并为促进髓鞘修复提供新的靶点。