COBRE: UL: STUDY THE ROLE OF LINGO01 IN VIVO SPINAL CORD REPAIR (SUB PKC)

COBRE：UL：研究 LINGO01 在体内脊髓修复中的作用 (SUB PKC)

• 批准号: 7609762
• 负责人: CHRISTOPHER B SHIELDS
• 金额: $ 23.44万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609762
• 关键词: Antibodies; Area; Axon; Centers of Research Excellence; Complex; Computer Retrieval of Information on Scientific Projects Database; Condition; Contusions; Demyelinations; Funding; Grant; Institution; Mus; Mutation; Myelin; Numbers; Oligodendroglia; Rate; Regulation; Reporting; Research; Research Personnel; Research Project Grants; Resources; Role; Signal Transduction; Site; Source; Spinal Cord; Spinal cord injury; Thick; Time; United States National Institutes of Health; Western Blotting; axon growth; axon regeneration; behavior test; central pattern generator; functional improvement; in vivo; in vivo Model; insight; myelination; precursor cell; prevent; receptor; repaired; spinal cord repair

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have changed the direction of our research project since the last report. LINGO-1, an inhibitory molecule and part of the Nogo receptor complex, is involved in CNS repair following spinal cord injury (SCI). This molecule transduces inhibitory signals intracellularly resulting in inhibition of axon growth. LINGO-1 signaling is modulated using LINGO-1 KO mice, DN LINGO-1, and LINGO-1 antibody in vivo (we demonstrated that DN LINGO-1 inhibition enhances the rate of MEP return following SCI). We hypothesize that negative regulation of LINGO-1 will enhance axon regrowth, remyelination, and functional improvement. LINGO-1 manipulation in vivo SCI may provide new strategies to treat SCI. We will study LINGO-1 expression under normal conditions and following SCI at different points in time and topographic sites. Temporal expression of LINGO-1 will be studied after contusion and demyelinating SCI (rRT-PCR 4hr, 1d, 3d. Western blot at 1d, 3d, 1wk. 3wks). This aim should provide insights into mammalian CNS LINGO-1 signal modulation after SCI. Negative regulation of LINGO-1 in experimental demyelination may increase the degree and rate of remyelination. Using a mouse spinal cord demyelination model in vivo, we will study whether axonal conduction, morphological, and behavioral tests, we asked whether LINGO-1 inhibition facilitates myelination. Does LINGO-1 mutation produces a greater number of immature oligodendrocytes and oligodendricytes precursor cells (OPC), or is myelin thickness enhanced? LINGO-1 reduces RhoA activation that prevents axon regeneration. We hypothesize that RhoA is upregulated during remyelination. We will also evaluate the effect of LINGO-1 inhibition on axon regeneration and collateral sprouting in a region remote from the SCI, specifically in the area of the central pattern generator (CPG) in the thoracolumbar area of the spinal cord.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 自上次报告以来，我们已经改变了研究项目的方向。LINGO-1是一种抑制分子，是Nogo受体复合体的一部分，参与脊髓损伤(SCI)后的中枢神经系统修复。这种分子在细胞内传递抑制信号，从而抑制轴突生长。在体内，Lingo-1信号是由Lingo-1 KO小鼠、DN Lingo-1和Lingo-1抗体调节的(我们证明抑制DNLingo-1可以提高脊髓损伤后MEP的返回率)。我们假设LINGO-1的负调控将促进轴突再生、重新髓鞘形成和功能改善。体内操纵LINGO-1可能为脊髓损伤的治疗提供新的策略。 我们将研究Lingo-1在正常条件下和脊髓损伤后不同时间点和不同地形点的表达。将研究LINGO-1在挫伤和脱髓鞘脊髓损伤后的时间表达(RRT-PCR 4小时，1天，3天。免疫印迹检测1d、3d、1wk。3周)。这一目标将为研究脊髓损伤后哺乳动物中枢神经系统LINGO-1信号的调控提供依据。LINGO-1在实验性脱髓鞘过程中的负调控可能会增加髓鞘再生的程度和速度。利用体内小鼠脊髓脱髓鞘模型，我们将研究轴突传导、形态和行为测试，我们询问LINGO-1抑制是否促进髓鞘形成。Lingo-1突变是否会产生更多的未成熟少突胶质细胞和少突胶质前体细胞(OPC)，或者髓鞘厚度增加？Lingo-1减少了阻止轴突再生的RhoA激活。我们假设RhoA在再髓鞘形成过程中上调。我们还将评估LINGO-1抑制对远离脊髓损伤区域的轴突再生和侧枝萌发的影响，特别是在脊髓胸腰段的中央模式生成器(CPG)区域。