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
基本信息
- 批准号:7558228
- 负责人:
- 金额:$ 32.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AdultAstrocytesAxonBMP2 geneBehavioralBone Morphogenetic ProteinsCell Differentiation processCell TransplantsCiliary Neurotrophic FactorCoculture TechniquesComplexContusionsDataDemyelinationsDevelopmentEnvironmentFamilyGrowth FactorHealthcareIn VitroInjection of therapeutic agentInjuryLeadLesionModelingModificationMyelinNeuronsOligodendrogliaPatientsProcessProliferatingPublishingQuality of lifeRattusReactive InhibitionRecoveryRecovery of FunctionSeveritiesSignal TransductionSocietiesSpinal CordSpinal GangliaSpinal cord injuryTestingTherapeutic InterventionTimeTransplantationUndifferentiatedWorkastrogliosisbasebehavior testbone morphogenetic protein 2central nervous system injuryclinically relevantcombinatorialfunctional lossin vivoinhibitor/antagonistinjuredirradiationmyelinationnerve stem cellneurotrophic factornovel therapeuticsoligodendrocyte precursorprecursor cellprogenitorpublic health relevancerepairedresponse to injurysuccesstranscription factor
项目摘要
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):脱髓鞘的轴突长期存在于受损的脊髓中,脱髓鞘但完整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。成年脊髓具有有限的自发髓鞘再生能力,尽管事实上具有髓鞘再生能力的少突胶质细胞前体细胞(OPC)响应于损伤而变得活跃和增殖。内源性OPCs的分化和髓鞘再生在损伤的脊髓中受到抑制。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地增加SCI后的髓鞘再生,但成功程度不同。大多数移植的神经干细胞分化为星形胶质细胞,并且在损伤的脊髓中它们分化为少突胶质细胞(OL)或神经元受到抑制。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成星形胶质细胞。了解损伤脊髓中内源性和移植的NSC或OPCs的分化和髓鞘再生的限制机制将导致新的治疗策略来修复SCI。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的分化和髓鞘再生。我们的初步数据表明,从损伤的脊髓反应性星形胶质细胞抑制OL分化的成人OPCs通过增加骨形态发生蛋白(BMPs)的表达。缺乏足够的信号刺激OPCs的分化和损伤脊髓中成熟OL的髓鞘形成也可能导致SCI后有限的髓鞘再生。我们的初步数据表明,增加生长因子如多神经营养因子D15 A或CNTF的表达促进了移植的OPCs在损伤脊髓中的髓鞘再生。我们推测,阻断抑制性BMP信号传导以促进OPC分化和增加生长因子的表达以增强其成熟和髓鞘再生的组合可能协同作用以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。在本申请中,我们将使用客观和敏感的电生理和行为分析,以测试这一假设在一个良好的特点化学脱髓鞘模型,也临床相关的挫伤性脊髓损伤模型在成年大鼠。根据我们公布的和初步的数据,提出了四个具体目标:1。目的:探讨脊髓损伤后星形胶质细胞是否通过增加骨形态发生蛋白的分泌而抑制成体OPCs的分化和髓鞘再生。2.为了验证阻断抑制性BMP信号传导将促进脱髓鞘脊髓中移植的成人OPCs的分化、成熟和髓鞘再生的假设。3.为了验证这一假设,即阻断抑制性BMP信号传导以促进分化和增加增强OL成熟和髓鞘形成的生长因子的表达的组合将协同作用以促进移植的成人OPCs的分化、成熟和髓鞘再生以及脱髓鞘脊髓中的功能恢复。4.为了测试在目标1-3中建立的最佳组合策略是否将通过移植的OPC导致更广泛的髓鞘再生以及在更临床相关的挫伤SCI模型中的进一步功能恢复。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,是社会上一个重大的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。在本研究中,我们将使用组合策略来促进成年大鼠临床相关的挫伤性SCI模型的髓鞘再生和功能恢复。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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{{ truncateString('QI LIN CAO', 18)}}的其他基金
In Vivo Reprogramming of Reactive Astrocyte and Chemogenetic Approach for SCI Repair
反应性星形胶质细胞的体内重编程和用于 SCI 修复的化学遗传学方法
- 批准号:
10553974 - 财政年份:2022
- 资助金额:
$ 32.68万 - 项目类别:
In vivo reprogramming of reactive astrocyte and chemogenetic approach for SCI repair.
反应性星形胶质细胞的体内重编程和用于 SCI 修复的化学遗传学方法。
- 批准号:
10176608 - 财政年份:2017
- 资助金额:
$ 32.68万 - 项目类别:
In vivo reprogramming of reactive astrocyte and chemogenetic approach for SCI repair.
反应性星形胶质细胞的体内重编程和用于 SCI 修复的化学遗传学方法。
- 批准号:
9384465 - 财政年份:2017
- 资助金额:
$ 32.68万 - 项目类别:
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 - 财政年份:2008
- 资助金额:
$ 32.68万 - 项目类别:
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 - 财政年份:2008
- 资助金额:
$ 32.68万 - 项目类别:
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:
8242791 - 财政年份:2008
- 资助金额:
$ 32.68万 - 项目类别:
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 - 财政年份:2008
- 资助金额:
$ 32.68万 - 项目类别:
REMYLINATION AS A MECHANISM FOR SPINAL CORD REPAIR
髓鞘再生作为脊髓修复机制
- 批准号:
7720379 - 财政年份:2008
- 资助金额:
$ 32.68万 - 项目类别:
REMYLINATION AS A MECHANISM FOR SPINAL CORD REPAIR
髓鞘再生作为脊髓修复机制
- 批准号:
7609764 - 财政年份:2007
- 资助金额:
$ 32.68万 - 项目类别:
REMYLINATION AS A MECHANISM FOR SPINAL CORD REPAIR
髓鞘再生作为脊髓修复机制
- 批准号:
7381134 - 财政年份:2006
- 资助金额:
$ 32.68万 - 项目类别:
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