Factors Affecting Regeneration Through the Glial Scar

描述(由申请人提供)：根据克里斯托弗和达纳·里夫基金会的数据，美国有100多万人患有脊髓损伤(SCI)。制定促进脊髓损伤后再生和功能恢复的策略一直是一个长期而具有挑战性的目标。尽管我们的实验室是第一个认识到硫酸化蛋白多糖在再生失败中的关键作用的实验室，但产生这一家族抑制性细胞外基质分子的细胞阻止再生的机制在很大程度上尚不清楚。再生的轴突，尽管营养不良，持续并紧密地与病变核心的一群前体细胞联系在一起，产生一种被认为是潜在的抑制性蛋白多糖，称为NG2。这些NG2细胞和据称是再生失败的主要蛋白多糖的作用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的高度优先生长如何导致粘附性捕获现象，这可能是再生失败的关键决定因素。我们建议的研究还将建立在神经元上一系列受体的令人兴奋的发现的基础上，我们提出通过过于强大的黏附机制来介导CSPGs的抑制作用。深入了解导致轴突长期卡在胶质疤痕内的复杂的细胞和分子相互作用，将使我们能够设计出改进的技术来阻止或克服这些不利的相互作用，并有助于寻找策略，以刺激胶质瘢痕以外的强大再生。) 公共卫生相关性：在多种形式的中枢神经系统创伤后形成的胶质瘢痕是轴突再生和功能恢复的主要障碍，因为病变附近的某些反应性胶质细胞产生了一系列强有力的抑制性细胞外基质分子，即硫酸软骨素蛋白多糖(CSPGs)。我们与John Flanagan实验室一起发现了第一个已知的神经元上介导这些分子抑制效应的受体，这一令人兴奋的发现为生产特定的封闭肽和基因敲除小鼠打开了大门，这些小鼠可以用于测试这些受体的遗传消融或药物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，由病变核心中特定数量的前体细胞-NG2胶质细胞产生的一个关键的CSPG实际上是如何通过创造营养不良和抑制潜在再生轴突的状态来阻止再生的。我们提出的研究将不仅阐明再生失败的基本机制，而且还将测试促进脊髓损伤后再生的新的潜在治疗策略。)

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.)