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（由申请人提供）：少突胶质细胞前体（OPC）分化为少突胶质细胞，少突胶质细胞是脊椎动物中枢神经系统的髓鞘形成细胞。髓鞘包裹大脑和脊髓中的轴突，维持轴突功能并促进电脉冲的快速传导。髓鞘的任何损伤，例如多发性硬化症中发生的损伤，都会导致轴突传导丧失，最终导致轴突变性和不可逆的神经功能障碍，从而导致严重的身体或精神损伤。多发性硬化症是一种毁灭性的疾病，影响着美国超过 300,000 人。目前的疗法旨在调节疾病的炎症方面，但长期功能恢复将取决于中枢神经系统髓磷脂的成功修复。最近的研究表明，多发性硬化症患者大脑中的许多脱髓鞘区域都含有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，详细了解控制 OPC 成熟和髓鞘形成的机制将为增强多发性硬化症的髓鞘修复提供新的见解和新的治疗策略。本提案中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) 及其共激活剂 p35/p39 在调节 OPC 发育、髓鞘形成和髓鞘再生中的作用。已知 Cdk5 参与对中枢神经系统发育至关重要的各种信号传导途径。我们的初步数据揭示了 Cdk5 在控制 OPC 和髓鞘形成发育方面的新功能。拟议的研究将利用分子和遗传学方法探索少突胶质细胞谱系细胞内的 Cdk5 是否在体外和体内调节其发育和髓鞘形成。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 通路是否是治疗开发的新的潜在靶点，我们将测试 Cdk5 是否对于诱导局灶性脱髓鞘病变后成人 CNS 的髓鞘再生至关重要。为了实现这一目标，我们将在脱髓鞘过程中选择性地从成人 CNS 的 OPC 中删除 Cdk5。成功完成拟议研究将为调节 OPC 成熟和髓鞘形成的信号机制提供重要见解，并提供促进髓鞘修复的新靶点。