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: 7809350
• 负责人: QI LIN CAO
• 金额: $ 23.45万
• 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/7809350
• 关键词: Spinal cord injury

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）：脱髓鞘轴突长期存在于受伤的脊髓中，脱髓鞘但完整的轴突的髓鞘再生代表了促进 SCI 后功能恢复的重要修复策略。尽管具有髓鞘再生能力的少突胶质细胞前体细胞（OPC）会因损伤而变得活跃并增殖，但成人脊髓自发髓鞘再生的能力有限。受损脊髓中内源性 OPC 的分化和髓鞘再生受到抑制。神经干细胞 (NSC) 或神经胶质祖细胞的移植也被证明可以有效增加 SCI 后的髓鞘再生，但成功程度各不相同。大多数移植的 NSC 分化为星形胶质细胞，并且它们向少突胶质细胞 (OL) 或神经元的分化在受损的脊髓中受到抑制。类似地，移植的神经胶质祖细胞的分化在受损的脊髓中也受到限制，并且许多移植的神经胶质祖细胞保持未分化或分化为星形胶质细胞。了解损伤脊髓中限制内源性和移植的 NSC 或 OPC 分化和髓鞘再生的机制应该会导致修复 SCI 的新治疗策略。损伤微环境中抑制因子的存在可能有助于限制少突胶质细胞分化和髓鞘再生。我们的初步数据表明，来自受损脊髓的反应性星形胶质细胞通过增加骨形态发生蛋白（BMP）的表达来抑制成体 OPC 的 OL 分化。损伤脊髓中缺乏足够的信号来刺激 OPC 分化和成熟 OL 的髓鞘形成也可能导致 SCI 后髓鞘再生有限。我们的初步数据表明，生长因子（例如多神经营养蛋白 D15A 或 CNTF）表达的增加促进了受损脊髓中移植 OPC 的髓鞘再生。我们假设，阻断抑制性 BMP 信号传导以促进 OPC 分化，并增加生长因子的表达以增强其成熟和髓鞘再生，可能会协同作用，促进更广泛的髓鞘再生，并导致 SCI 后更大的电生理和运动行为恢复。在此应用中，我们将使用客观且灵敏的电生理学和行为分析，在成熟大鼠的充分表征的化学脱髓鞘模型以及临床相关的挫伤性 SCI 模型中检验这一假设。根据我们已发表的初步数据，提出了四个具体目标： 1. 确定来自受损脊髓的星形胶质细胞是否通过增加 BMP 分泌来抑制成体 OPC 的分化和髓鞘再生。 2. 验证阻断抑制性 BMP 信号传导将促进脱髓鞘脊髓中移植的成体 OPC 的分化、成熟和髓鞘再生的假设。 3. 验证以下假设：阻断抑制性 BMP 信号传导以促进分化，并增加促进 OL 成熟和髓鞘形成的生长因子的表达，将协同促进移植的成体 OPC 的分化、成熟和髓鞘再生以及脱髓鞘脊髓的功能恢复。 4. 测试目标 1-3 中建立的最佳组合策略是否会导致移植的 OPC 更广泛的髓鞘再生以及在临床更相关的挫伤 SCI 模型中进一步的功能恢复。公共卫生相关性：脊髓损伤对患者及其家人来说是毁灭性的伤害，也是社会的重大医疗保健和经济负担。恢复部分功能的治疗干预将提高这些患者的生活质量。在本提案中，我们将采用组合策略促进成年大鼠临床相关挫伤性 SCI 模型中的髓鞘再生和功能恢复。