Combinatory strategies to functional remyelination after spinal cord injury

脊髓损伤后功能性髓鞘再生的组合策略

• 批准号: 7438512
• 负责人: QI LIN CAO
• 金额: $ 7.72万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7438512
• 关键词: Adult; Astrocytes; Axon; BMP2 gene; Behavioral; Bone Morphogenetic Proteins; Cell Differentiation process; Cell Transplants; Ciliary Neurotrophic Factor; Coculture Techniques; Complex; Contusions; Data; Demyelinations; Development; Environment; Family; Growth Factor; Healthcare; In Vitro; Injection of therapeutic agent; Injury; Lead; Lesion; Modeling; Modification; Myelin; Neurons; Oligodendroglia; Patients; Process; Proliferating; Public Health; Publishing; Quality of life; Rattus; Reactive Inhibition; Recovery; Recovery of Function; Severities; Signal Transduction; Societies; Spinal Cord; Spinal Ganglia; Spinal cord injury; Testing; Therapeutic Intervention; Time; Transplantation; Undifferentiated; Work; astrogliosis; base; behavior test; bone morphogenetic protein 2; central nervous system injury; clinically relevant; combinatorial; functional loss; in vivo; inhibitor/antagonist; injured; irradiation; myelination; nerve stem cell; neurotrophic factor; novel therapeutics; oligodendrocyte precursor; precursor cell; progenitor; repaired; response to injury; success; transcription factor

DESCRIPTION (provided by applicant): Demyelinated axons persist in the injured spinal cord chronically, and remyelination of demyelinated, but otherwise intact axons, represents an important repair strategy to facilitate functional recovery after SCI. Adult spinal cord has a limited capacity to spontaneously remyelinate, despite the fact that oligodendrocyte precursor cells (OPCs), which have the capacity to remyelinate, become active and proliferate in response to the injury. The differentiation of, and remyelination by endogenous OPCs is inhibited in the injured spinal cord. Transplantation of neural stem cells (NSCs) or glial progenitors has also proven effective to increase remyelination after SCI, but with varying degrees of success. The majority of grafted NSCs differentiate into astrocytes and their differentiation into oligodendrocytes (OLs) or neurons is inhibited in the injured spinal cord. Similarly, differentiation from grafted glial progenitors is also restricted in the injured spinal cord, and many transplanted glial progenitors remain undifferentiated or differentiate into astrocytes. Understanding the mechanism(s) that restrict the differentiation of and remyelination by the endogenous and grafted NSC or OPCs in the injured spinal cord should lead to new therapeutic strategies to repair SCI. The presence of inhibitory factors in the injury microenvironment may contribute to the restriction of the oligodendrocyte differentiation and remyelination. Our preliminary data showed that reactive astrocytes from the injured spinal cord inhibit OL differentiation of adult OPCs by increasing expression of bone morphogenetic proteins (BMPs). The absence of sufficient signals to stimulate differentiation of OPCs and myelination by mature OLs in the injured spinal cord may also contribute to the limited remyelination after SCI. Our preliminary data showed that increasing expression of growth factors such as the multi- neurotrophin D15A or CNTF promoted the remyelination by grafted OPCs in the injured spinal cord. We hypothesize that the combination of blocking inhibitory BMP signaling to promote OPC differentiation and increasing the expression of growth factors to enhance their maturation and remyelination may work synergistically to promote more extensive remyelination, and lead to greater electrophysiological and locomotor behavioral recovery after SCI. In this application, we will use objective and sensitive electrophysiological and behavioral analyses to test this hypothesis in a well characterized chemically demyelinated model and also clinically-relevant contusive SCI model in adult rats. Based on our published and preliminary data, four specific aims are proposed: 1. To determine whether astrocytes from the injured spinal cord inhibit differentiation of and remyelination by adult OPCs by increased secretion of BMPs. 2. To test the hypothesis that blocking inhibitory BMP signaling will promote the differentiation, maturation, and remyelination of grafted adult OPCs in the demyelinated spinal cord. 3. To test the hypothesis that combination of blocking inhibitory BMP signaling to promote the differentiation and increasing the expression of growth factors that enhance the maturation of and myelination by OLs will work synergistically to promote the differentiation, maturation, and remyelination of grafted adult OPCs and functional recovery in the demyelinated spinal cord. 4. To test whether the optimal combinatorial strategies, established in Aims 1-3, will lead to more extensive remyelination by transplanted OPCs and further functional recovery in the more clinically relevant contusion SCI model. PUBLIC HEALTH RELEVANCE: Spinal cord injury is a devastating injury for patients and their families and is a significant health care and financial burden on society. Therapeutic intervention(s) that would restore partial function would increase the quality of life of those patients. In this proposal, we will use combinatorial strategy to promote remyelination and functional recovery in clinically-relevant contusive SCI model in adult rats.

描述(申请人提供)：脱髓鞘轴突在损伤的脊髓中持续存在，脱髓鞘的轴突重新髓鞘形成，但其他方面是完整的，是促进脊髓损伤后功能恢复的重要修复策略。成人脊髓自发再生髓鞘的能力有限，尽管具有再生髓鞘能力的少突胶质前体细胞(OPC)在损伤后变得活跃和增殖。在损伤的脊髓中，内源性OPC的分化和再髓鞘形成受到抑制。神经干细胞(NSCs)或神经胶质前体细胞移植也被证明有效地增加了脊髓损伤后的再髓鞘形成，但成功程度各不相同。大多数移植的神经干细胞分化为星形胶质细胞，其向损伤脊髓内的少突胶质细胞或神经元的分化受到抑制。同样，移植的神经胶质前体细胞在损伤的脊髓中的分化也受到限制，许多移植的神经胶质前体细胞仍未分化或分化为星形胶质细胞。了解内源性神经干细胞或OPC限制损伤脊髓分化和再髓鞘形成的机制(S)，将为脊髓损伤的修复提供新的治疗策略。损伤微环境中抑制因子的存在可能是限制少突胶质细胞分化和再髓鞘形成的原因之一。我们的初步数据显示，来自损伤脊髓的反应性星形胶质细胞通过增加骨形态发生蛋白(BMPs)的表达来抑制成年OPC的OL分化。脊髓损伤后缺乏足够的信号来刺激OPC的分化和成熟的OCs的髓鞘形成也可能是脊髓损伤后髓鞘再生受限的原因之一。我们的初步数据表明，多神经营养因子D15A或CNTF等生长因子的表达增加促进了移植的OPC在损伤脊髓中的重新髓鞘形成。我们推测，阻断抑制BMP信号以促进OPC分化和增加生长因子的表达以促进其成熟和再髓鞘形成可能协同作用，促进更广泛的再髓鞘形成，并导致脊髓损伤后更大的电生理和运动行为的恢复。在这项应用中，我们将使用客观和灵敏的电生理和行为分析来验证这一假设，在一个具有良好特征的化学脱髓鞘模型和临床相关的成年大鼠脊髓挫伤模型中。根据我们已发表的和初步的数据，我们提出了四个具体的目标：1.确定损伤脊髓的星形胶质细胞是否通过增加BMPs的分泌来抑制成体OPC的分化和再髓鞘形成。2.验证阻断抑制BMP信号通路将促进脱髓鞘内移植的成体OPC分化、成熟和再髓鞘形成的假说。3.验证阻断抑制BMP信号促进OPC分化和增加促进OCs成熟和髓鞘形成的生长因子的表达将协同促进移植的OPC分化、成熟和再髓鞘形成和脱髓鞘脊髓功能恢复的假说。4.在更具临床相关性的挫伤脊髓损伤模型中，测试AIMS 1-3中建立的最佳组合策略是否会导致移植的OPC更广泛的再髓鞘形成和进一步的功能恢复。公共卫生相关性：脊髓损伤对患者及其家人来说是一种毁灭性的伤害，是社会的重大医疗保健和经济负担。部分功能恢复的治疗性干预(S)将提高患者的生活质量。在这个方案中，我们将使用组合策略来促进临床相关的成年大鼠挫伤脊髓损伤模型的再髓鞘形成和功能恢复。