Factors Affecting Regeneration Through the Glial Scar

影响神经胶质疤痕再生的因素

• 批准号: 8235242
• 负责人: Jerry Silver
• 金额: $ 34.34万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8235242
• 关键词: Ablation; Adhesions; Adhesives; Adult; Affect; Afferent Neurons; Animals; Antibodies; Astrocytes; Axon; Behavior; Binding; Biological Assay; CSPG4 gene; Cell surface; Cells; Chondroitin Sulfate Proteoglycan; Chondroitinases; Chronic; Cicatrix; Coculture Techniques; Complex; Data; Distal; Enzymes; Extracellular Matrix; Failure; Family; Fibronectins; Fostering; Foundations; Genetic; Goals; Growth; Growth Cones; Hyaluronidase; Image; In Vitro; Inorganic Sulfates; Integrins; Knockout Mice; Label; Laminin; Lead; Lesion; Light; Mediating; Microscopy; Modeling; Mus; NG2 antigen; Natural regeneration; Neuroglia; Neurons; Peptides; Play; Population; Production; Proteoglycan; Rattus; Recovery of Function; Reporter; Resolution; Role; Sensory; Spinal cord injury; Spottings; Staging; Surface; Synapses; Techniques; Testing; Therapeutic; Time; Transgenic Mice; Traumatic CNS injury; Unspecified or Sulfate Ion Sulfates; aggrecan; axon regeneration; cell type; cohort; conditioning; dorsal column; extracellular; improved; in vitro Assay; in vivo; multi-photon; precursor cell; preference; receptor; research study; sciatic nerve; synaptogenesis; tissue fixing

DESCRIPTION (provided by applicant): According to the Christopher and Dana Reeve Foundation there are more than 1 million people with spinal cord injury (SCI) in the US. Developing strategies to promote regeneration and functional recovery after SCI has been a long and challenging goal. Although our lab was the first to recognize the critical role of sulfated proteoglycans in regeneration failure, the mechanisms by which the cells that produce this family of inhibitory extracellular matrix molecules block regeneration is largely unknown. Regenerating, albeit dystrophic, axons continually and tightly associate with a cohort of precursor cells in the core of the lesion that produce what is thought to be a potently inhibitory proteoglycan called NG2. The role of these NG2 cells and what has been purported to be a major proteoglycan in regeneration failure has become highly controversial. Our proposed studies will reveal for the first time how such highly preferred growth upon the surface of these cells results in an adhesive entrapment phenomenon that is likely to be a critical determinant in regeneration failure. Our proposed studies will also build upon the exciting discovery of a family of receptors on neurons that mediate, we propose via overly strong adhesive mechanisms, the inhibitory actions of CSPGs. Understanding in depth the complicated cellular and molecular interactions that lead to long term entrapment of axons within the glial scar will allow us to devise improved techniques for blocking or overcoming these untoward interactions and help in the search for strategies to stimulate robust regeneration beyond the glial scar.) PUBLIC HEALTH RELEVANCE: The glial scar that develops after many forms of CNS trauma is a major obstacle to axon regeneration and functional recovery because of the production by certain reactive glial cells in the vicinity of the lesion of a family of potently inhibitory extracellular matrix molecules known as the chondroitin sulfate proteoglycans (CSPGs). Our exciting discovery with the John Flanagan lab of the first known receptors on neurons that mediate the inhibitory effects of these molecules has opened the door to the production of specific blocking peptides and knockout mice that can be used to test the effect of genetic ablation or pharmacological manipulation of these receptors on axon regeneration. Our exciting preliminary data also suggest for the first time how one critical CSPG, produced by a particular population of precursor cells in the lesion core, the NG2 glia, actually function to block regeneration by creating a state of dystrophy and entrapment of the would-be regenerating axon. Our proposed studies will shed light not only on the fundamental mechanisms of regeneration failure but also test new and potentially therapeutic strategies to foster regeneration after spinal cord injury.)

描述（由申请人提供）：根据克里斯托弗和达纳里夫基金会有超过100万人脊髓损伤（SCI）在美国。制定策略以促进SCI后的再生和功能恢复一直是一个长期且具有挑战性的目标。虽然我们的实验室是第一个认识到硫酸化蛋白聚糖在再生失败中的关键作用，但产生这种抑制性细胞外基质分子家族的细胞阻断再生的机制在很大程度上是未知的。再生，虽然营养不良，轴突持续和紧密地与一群前体细胞在病变的核心，产生什么被认为是一个强大的抑制蛋白聚糖称为NG2。这些NG2细胞的作用和据称是再生失败中的主要蛋白聚糖已经变得非常有争议。我们提出的研究将首次揭示这些细胞表面上的这种高度优先生长如何导致粘合剂截留现象，这可能是再生失败的关键决定因素。我们提出的研究还将建立在神经元上的一个受体家族的令人兴奋的发现的基础上，我们提出通过过强的粘附机制来介导CSPGs的抑制作用。深入了解导致轴突长期滞留在胶质瘢痕内的复杂的细胞和分子相互作用，将使我们能够设计出用于阻断或克服这些不良相互作用的改进技术，并有助于寻找刺激胶质瘢痕之外的强大再生的策略。 公共卫生相关性：在许多形式的CNS创伤后发展的神经胶质瘢痕是轴突再生和功能恢复的主要障碍，这是因为在被称为硫酸软骨素蛋白聚糖（CSPG）的有力抑制性细胞外基质分子家族的损伤附近的某些反应性神经胶质细胞产生。我们与John Flanagan实验室一起激动人心地发现了神经元上第一个已知的受体，这些受体介导这些分子的抑制作用，这为生产特异性阻断肽和敲除小鼠打开了大门，这些小鼠可用于测试这些受体的遗传消融或药理学操作对轴突再生的影响。我们令人兴奋的初步数据还首次表明，由病变核心中的特定前体细胞群体产生的一种关键CSPG，即NG2胶质细胞，实际上是如何通过产生营养不良状态和捕获将要再生的轴突来阻止再生的。我们提出的研究不仅将揭示再生失败的基本机制，而且还将测试新的和潜在的治疗策略，以促进脊髓损伤后的再生。