Novel molecular mediators for activity-dependent myelination

活性依赖性髓鞘形成的新型分子介质

• 批准号: 10622530
• 负责人: Wenjing Sun
• 金额: $ 37.95万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622530
• 关键词: Ablation; Action Potentials; Adult; Affinity; Anatomy; Axon; Behavior assessment; Behavioral; Binding; Biochemical; Calcium Channel; Cell Differentiation process; Cell Proliferation; Cell membrane; Cells; Central Nervous System; Cervical; Coculture Techniques; Data; Demyelinating Diseases; Demyelinations; Development; Disease; Electrophysiology (science); Ensure; Exhibits; Failure; Genes; Histologic; Immunohistochemistry; Impairment; In Vitro; Injury; Knockout Mice; Length; Lysophosphatidylcholines; Mammals; Mediating; Mediator; Modeling; Molecular; Molecular Target; Motor; Multiple Sclerosis; Mus; Myelin; Myelin Proteins; Myelin Sheath; Nervous System Physiology; Neurologic; Neurons; Oligodendroglia; Pathway interactions; Pattern; Presynaptic Terminals; Process; Proliferating; Proteins; Publishing; Recovery of Function; Role; Sensory; Series; Signal Transduction; Speed; Spinal Cord; Synapses; Synaptic Transmission; Synaptic Vesicles; Tamoxifen; Techniques; Testing; Therapeutic; Therapeutic Intervention; Thick; Transgenic Mice; Translational Research; Trauma; Traumatic CNS injury; Travel; biophysical properties; cell behavior; central nervous system injury; conditional knockout; design; dorsal column; experimental study; gabapentin; gain of function; genetic approach; imaging approach; improved; in vivo; interdisciplinary approach; loss of function; myelination; nervous system development; neural network; neurotransmission; neurotransmitter release; novel; oligodendrocyte lineage; oligodendrocyte precursor; overexpression; pharmacologic; precursor cell; presynaptic; promoter; remyelination; repaired; spatiotemporal; therapeutically effective; transcriptomics; transmission process; vesicular release; viral gene delivery; voltage

ABSTRACT The majority of axons in the central nervous system (CNS) are wrapped with compact layers of myelin sheaths to ensure the rapid transmission of neuronal signals over long distances. As myelin thickness and sheath length have profound effects on conduction velocity, myelination is also crucial to the precise control of spatiotemporal activity patterns in the CNS. In the mammalian spinal cord, both descending motor and ascending sensory pathways travel over long distances, requiring fine control of conduction speed necessary for sensory-motor integration. Myelin disruption in the spinal cord after CNS trauma or disease, like multiple sclerosis, causes axonal conduction failure leading to severe impairment of neurological function. Accumulating data support the notion that neuronal activity positively regulates myelin development and also induces adaptive myelin plasticity in adulthood. However, the underlying mechanisms are still not fully understood, and no molecular mediators have been identified regulating this process. Alpha2delta1 (A2d1) subunits of voltage-gated Ca2+ channels (VGCCs) positively regulate the plasma membrane expression and the biophysical properties of VGCCs, including those controlling synaptic vesicle release. Our preliminary data suggest that A2d1 subunits positively regulate myelin development in the murine spinal cord. Building on our promising data, the proposed study aims at dissecting the neuronal- and glial-specific mechanisms underlying the role of A2d1 subunits in myelin development and repair. We propose a series of gain- and loss-of-function experiments to investigate how A2d1 subunits expressed in neurons and oligodendrocyte precursor cells positively regulate myelin development. Additionally, we will test whether manipulating A2d1 subunits effectively promotes remyelination and functional recovery after demyelinating injury. Overall, this study will shed light on the molecular mechanisms underlying activity-dependent myelin formation and plasticity and contribute to the design of translational research aimed at restoring myelin and neurological function after CNS trauma and disease.

摘要