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: 8043501
• 负责人: QI LIN CAO
• 金额: $ 31.43万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8043501
• 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; Health; Healthcare; In Vitro; Injection of therapeutic agent; Injury; Lead; Lesion; Modeling; Modification; Myelin; Neurons; Oligodendroglia; Patients; Process; Proliferating; 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; 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; overexpression; 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（由申请人提供）：受损脊髓中长期存在脱髓鞘轴突，脱髓鞘轴突的再髓鞘化是促进脊髓损伤后功能恢复的重要修复策略。成人脊髓自发髓鞘再生成的能力有限，尽管少突胶质前体细胞（OPCs）具有髓鞘再生成能力，在损伤后变得活跃和增殖。内源性OPCs的分化和髓鞘再生在损伤脊髓中受到抑制。神经干细胞（NSCs）或神经胶质祖细胞移植也被证明能有效增加脊髓损伤后的髓鞘再生，但成功率不同。大多数移植的NSCs分化为星形胶质细胞，其向少突胶质细胞（OLs）或神经元的分化在损伤脊髓中受到抑制。同样，从移植的神经胶质祖细胞向受损脊髓的分化也受到限制，许多移植的神经胶质祖细胞未分化或分化为星形胶质细胞。了解损伤脊髓内源性和移植的NSC或OPCs的分化和再髓鞘形成的限制机制，将为修复脊髓损伤提供新的治疗策略。损伤微环境中抑制因子的存在可能限制了少突胶质细胞的分化和髓鞘再生。我们的初步数据表明，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OPCs的OL分化。损伤脊髓中缺乏足够的信号来刺激OPCs的分化和成熟ol的髓鞘形成，也可能是脊髓损伤后髓鞘再生有限的原因。我们的初步数据表明，增加多神经营养因子D15A或CNTF等生长因子的表达可促进损伤脊髓移植OPCs的再髓鞘形成。我们推测，阻断抑制BMP信号通路促进OPC分化和增加生长因子表达促进其成熟和髓鞘再生可能协同作用，促进更广泛的髓鞘再生，并导致脊髓损伤后更大的电生理和运动行为恢复。在这项应用中，我们将使用客观和敏感的电生理和行为分析，在一个具有良好特征的化学脱髓鞘模型和成年大鼠临床相关的挫伤性脊髓损伤模型中验证这一假设。根据我们公布的和初步的数据，提出了四个具体目标：1。研究损伤脊髓的星形胶质细胞是否通过增加bmp分泌抑制成年OPCs的分化和髓鞘再生。2. 为了验证阻断抑制BMP信号传导将促进脱髓鞘脊髓中移植成人OPCs的分化、成熟和再髓鞘形成的假设。3. 为了验证阻断抑制BMP信号促进分化和增加生长因子表达促进OLs成熟和髓鞘形成的联合作用将协同促进成人移植OPCs的分化、成熟和髓鞘再生以及脱髓鞘脊髓功能恢复的假设。4. 为了测试Aims 1-3中建立的最佳组合策略是否会在更具临床相关性的挫伤性脊髓损伤模型中导致移植的OPCs更广泛的髓鞘再生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属来说是一种毁灭性的伤害，是社会的重大卫生保健和经济负担。恢复部分功能的治疗干预将提高这些患者的生活质量。在本研究中，我们将采用组合策略来促进成年大鼠临床相关的挫伤性脊髓损伤模型的髓鞘再生和功能恢复。