Plasticity of intact circuits restores function after a spinal cord injury.

描述（由申请人提供）： 创伤后CNS轴突不能再生和重新神经支配适当的靶点导致功能的慢性损害，这对TBI、MS、中风和SCI患者来说是毁灭性的预后。无数的研究已经鉴定了两大类负责轴突生长停滞的轴突生长抑制剂（AGI）蛋白，髓鞘相关抑制剂（Nogo、MAG、OMgp）和硫酸软骨素蛋白聚糖（CSPG）。否定这些抑制剂在体内的活性的实验范例已经显示出受损轴突的再生略有增加，但功能的恢复更显着。在治疗方案进入临床之前，有必要确定抗AGI策略恢复功能的机制。长距离再生介导的功能恢复的另一种假设是SCI后通常保留的完整脊髓回路的重组。该提案的中心目标是全面评估完整脊髓回路取代失去的连接的潜力，并进一步确定否定AGIs的作用是否支持适应性或适应不良的轴突重组。使用解剖学，电生理学，遗传学和体内成像方法的组合，我们计划描绘完整的脊髓回路的塑性潜力。耶鲁大学的神经病学系独特地定位于促进这些研究，因为它拥有世界一流的教师和尖端的核心设施，包括多光子体内成像技术和小鼠转基因设施。作为博士后，我在耶鲁大学接受了分子和细胞生物学方面的持续培训，这对我在英国伦敦国王学院攻读博士学位期间掌握的整体动物生理学技能起到了独特的作用。在Stephen Strittmatter教授的认真指导下，我的直接目标是应用这些有效的技能来回答CNS轴突再生领域中存在的一些基本问题，例如;长距离再生对于功能重演是必要的吗？成人中枢神经系统是否由于抑制蛋白的持续表达而受到生长抑制？此外，成年人的中枢神经系统在受伤时是否有可塑性的应急计划？从长远来看，我的总体目标是建立一个独立的研究实验室，并继续追求我的最终目标，即协助设计SCI患者的治疗策略。 总之，我们计划使用解剖学，电生理学，遗传学和体内成像方法来定义完整脊髓回路内的可塑性程度，并研究脊髓损伤后从头回路恢复功能的能力，从而减少每个年龄组，社会各阶层，世界各地的人们所承受的这种神经系统疾病的负担。

DESCRIPTION (provided by applicant): The inability of CNS axons to regenerate and reinnnervate appropriate targets after trauma results in chronic compromise of function, which presents a devastating prognosis for TBI, MS, stroke and SCI patients. Myriad studies have identified two broad classes of axon growth inhibitor (AGI) proteins responsible for axon growth arrest, the myelin associated inhibitors (Nogo, MAG, OMgp) and the Chondroitin Sulfate Proteoglycans (CSPGs). Experimental paradigms that negate the activity of these inhibitors in vivo have shown a slight increase in regeneration of damaged axons, but a more dramatic restitution of function. Before therapeutic options move into the clinic it is necessary to define the mechanism whereby anti-AGI strategies restore function. An alternative hypothesis to long distance regeneration-mediated restitution of function would be the reorganization of intact spinal circuitry that often remains after SCI. It is the central goal of this proposal to comprehensively evaluate the potential for intact spinal circuits to replace lost connections, and furthermore define whether negating the action of AGIs supports adaptive or maladaptive axonal reorganization. Using a combination of anatomical, electrophysiological, genetic and in vivo imaging methodology we plan to delineate the plastic potential of intact spinal circuitry. The Neurology department at Yale is inimitably positioned to facilitate these studies owing to its world-class faculty and the availability of cutting-edge core facilities, including multi-photon in vivo imaging technology and mouse transgenesis facilities. The continued training in molecular and cellular biology have I have received at Yale as a postdoctoral associate has uniquely complimented the whole-animal physiology skills that I mastered during my PhD at King's College London, UK. Under the earnest supervision of Prof. Stephen Strittmatter, it is my immediate goal to apply these potent skills to answering some of the fundamental questions that remain in the field of CNS axon regeneration, such as; is long distance regeneration necessary for recapitulation of function? Is the adult CNS under tonic growth inhibition due to the continued expression of inhibitor proteins? Furthermore is the adult CNS wired with contingent plans for plasticity in case of injury? In the long-term it is my overall goal to initiate an independent research lab and continue pursing my ultimate goal of assisting in the design of therapeutic strategies for SCI patients. In summary, we plan to use anatomical, electrophysiological, genetic and in vivo imaging methodology to define the extent of plasticity within intact spinal circuitry and investigate the capacity of de novo circuits to restore function after spinal cord and therefore reduce the burden of this neurological disease borne by every age group, by every segment of society, by people all over the world.