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

描述(由申请人提供)： 中枢神经系统轴突在创伤后不能再生和重新支配适当的靶点，导致慢性功能损害，这对脑外伤、多发性硬化、卒中和脊髓损伤患者来说是毁灭性的预后。大量研究已经确定了两大类轴突生长抑制蛋白(AGI)，它们是髓鞘相关抑制物(Nogo，MAG，OMGp)和硫酸软骨素蛋白多糖(CSPGs)。在体内否定这些抑制物活性的实验范式显示，受损轴突的再生略有增加，但功能恢复得更为戏剧性。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。远距离再生介导的功能恢复的另一种假说是脊髓损伤后经常保留的完整脊髓回路的重组。这项建议的中心目标是全面评估完整的脊髓环路取代丢失的连接的潜力，并进一步确定否定AGI的作用是否支持适应性或非适应性轴突重组。使用解剖学、电生理学、遗传学和活体成像方法的组合，我们计划描绘完整的脊髓神经回路的可塑性潜力。耶鲁大学神经病学系拥有世界一流的师资和尖端的核心设施，包括多光子活体成像技术和小鼠转基因设施，因此在促进这些研究方面具有无可比拟的优势。作为一名博士后，我在耶鲁大学继续接受分子和细胞生物学方面的培训，这对我在英国伦敦国王学院攻读博士期间所掌握的全动物生理学技能具有独特的赞誉。在斯蒂芬·斯特里特马特教授的认真指导下，我的直接目标是应用这些强大的技能来回答中枢神经系统轴突再生领域中仍然存在的一些基本问题，例如：长距离再生对于功能的重述是必要的吗？成人中枢神经系统是否由于抑制蛋白的持续表达而受到紧张性生长抑制？此外，成人中枢神经系统是否有在受伤情况下的可塑性应急计划？从长远来看，我的总体目标是创办一个独立的研究实验室，并继续追求我的最终目标，即协助设计脊髓损伤患者的治疗策略。 综上所述，我们计划使用解剖学、电生理学、遗传学和活体成像方法来定义完整脊髓回路内的可塑性程度，并研究新生回路在脊髓后恢复功能的能力，从而减轻这种神经疾病的负担，由每个年龄段、社会各个阶层和世界各地的人们承担。

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.