Intrinsic and extrinsic regulation of injury-induced axonal growth in the CNS: a combinatorial approach with known pathways and exploring the unknown role of microRNAs

中枢神经系统损伤诱导的轴突生长的内在和外在调节：已知途径的组合方法并探索 microRNA 的未知作用

• 批准号: 235777469
• 负责人: Dr. Oliver Tress
• 金额: --
• 依托单位: Department of Neurosciences
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/235777469?language=en
• 关键词: Intrinsic; extrinsic; regulation; injury; induced

Axon growth and regeneration are of key importance for functional recovery after spinal cord injury. Several mechanisms and molecular pathways that regulate axon growth and regeneration in the adult mammalian central nervous system (CNS) have been identified. PTEN (phosphatase and tensin homolog) negatively regulates the neuron-intrinsic growth capacity while the myelin derived axon growth inhibitors modulate the sprouting of spared axons. Furthermore, chondroitin sulfate proteoglycans (CSPGs) inhibit axon growth after spinal cord injury. Despite the advancement in our understanding of axon growth regulation, there is no cure or effective treatment to promote axon growth and functional recovery to date. Further understanding the interaction between the existing molecular targets and identifying novel molecular targets will allow for the development of effective therapeutic strategies. In the first project I will investigate the functional interplay between extrinsic factor-mediated inhibition and neuron-intrinsic regulation of axon growth after CNS injury. I will combine gene deletion of NgR1 (or Rtn4r; reticulon 4 receptor) and NgR3 (or Rtn4rl1; reticulon 4 receptor-like 1) (receptors for CSPGs and myelin derived axon growth inhibitors) with conditional PTEN deletion in order to assess the consequence on axon sprouting and regeneration in mouse models of CNS injuries. In a second project I aim to identify microRNAs (miRNAs) that regulate injury-induced axonal growth. MiRNAs are small non-coding RNAs of about 22 nucleotides length which post-transcriptionally regulate protein synthesis via interaction with target gene mRNA. I will start by assessing candidate miRNAs that target PTEN and other neuronally expressed regulators of axon growth. In vitro neurite outgrowth and axon regeneration assays and subsequently in vivo CNS injury models will be applied to investigate axon growth after manipulation of miRNA expression. While the first project will allow me to learn the field and contribute to building on existing knowledge in the field of CNS injury and repair, the second project will allow me to explore the unknown role of miRNAs in axon growth and spinal cord repair.

轴突的生长和再生是脊髓损伤后功能恢复的关键。成年哺乳动物中枢神经系统(CNS)中调节轴突生长和再生的几种机制和分子途径已经被确定。PTEN(磷酸酶和张力蛋白同系物)负向调节神经元的内在生长能力，而髓鞘衍生的轴突生长抑制物调节备用轴突的萌发。此外，硫酸软骨素蛋白多糖(CSPGs)可抑制脊髓损伤后轴突的生长。尽管我们对轴突生长调节的了解有所进展，但到目前为止还没有治愈或有效的治疗方法来促进轴突生长和功能恢复。进一步了解现有分子靶点之间的相互作用并识别新的分子靶点将有助于开发有效的治疗策略。在第一个项目中，我将研究中枢神经系统损伤后外源性因子介导的抑制和神经元内源性调节轴突生长之间的功能相互作用。我将把NgR1(或Rtn4r；网状4受体)和NgR3(或Rtn4rl1；网状4受体样1)(CSPGs和髓鞘衍生轴突生长抑制物的受体)的基因缺失与有条件的PTEN缺失结合起来，以评估对中枢神经系统损伤模型小鼠轴突萌发和再生的影响。在第二个项目中，我的目标是识别调节损伤诱导的轴突生长的微RNA(MiRNAs)。MiRNAs是一种长度约为22个核苷酸的非编码小RNA，它通过与靶基因mRNA的相互作用在转录后调节蛋白质的合成。我将首先评估针对PTEN和其他神经表达的轴突生长调节因子的候选miRNAs。体外轴突生长和轴突再生分析以及随后的体内中枢神经系统损伤模型将被应用于研究操纵miRNA表达后的轴突生长。虽然第一个项目将使我学习该领域，并在中枢神经系统损伤和修复领域现有知识的基础上做出贡献，但第二个项目将使我能够探索miRNAs在轴突生长和脊髓修复中的未知角色。