Nogo Receptor in Adult Central Nervous System Plasticity and Regeneration

描述（由申请人提供）：成人中枢神经系统轴突在损伤后不能发芽和生长，限制了广泛的神经系统疾病的恢复，包括脊髓损伤（SCI）、中风、头部创伤和慢性多发性硬化症。在过去的5年中，在确定限制成人中枢神经系统轴突生长的分子途径以及将这些知识转化为治疗机会方面取得了重大进展。在这个项目的最后一个周期中，我们发现Nogo-66受体（NgR）蛋白是髓鞘衍生蛋白、Nogo和MAG的配体结合受体。NgR功能的药理扰动或NgR位点的遗传破坏可以增强脊髓损伤后和中风后神经系统中某些纤维的轴突生长程度。我们发现这种中枢神经系统纤维的生长与运动功能的行为恢复改善有关。促进损伤恢复的成功使我们考虑髓磷脂抑制剂的生理作用而不是病理作用。我们发现，在没有损伤的情况下，经验依赖的皮质可塑性是由ngr依赖的机制控制的。虽然这项工作已经确定了调节成人中枢神经系统轴突发芽的一条途径，但它也提出了关于NgR功能的关键问题，这些问题将在该项目的第二个周期中得到解决。在拟议的工作中，我们将研究NgR在可塑性和再生中的解剖学、分子和时间特异性。我们将考虑核磁共振门控大脑可塑性的细胞基础。目前的假设是，NgR的功能是“锁定”神经元元素，防止解剖重排。NgR信号转导的分子基础也将在生物化学和遗传学上进行探讨。综上所述，这些研究将为NgR对成人中枢神经系统轴突可塑性和再生的作用机制和程度提供重要的见解。这些数据将使我们了解中枢神经系统内连接的稳定性，并阐明利用这些知识进行治疗干预的可能性。

DESCRIPTION (provided by applicant): The failure of adult CNS axons to sprout and to grow after injury limits recovery in a broad range of neurological conditions, including spinal cord injury (SCI), stroke, head trauma and chronic multiple sclerosis. Over the last 5 years, significant progress has been achieved towards defining the molecular pathways limiting adult CNS axon growth and towards translating this knowledge into therapeutic opportunities. During the last cycle of this project, we identified the Nogo-66 Receptor (NgR) protein as a ligand-binding receptor for the myelin-derived proteins, Nogo and MAG. Pharmacological perturbation of NgR function or genetic disruption of the NgR locus allows an enhanced degree of axonal growth for certain fibers in the post-SCI and post-stroke nervous system. We showed that such CNS fiber growth is associated with improved behavioral recovery of motor function. Success in promoting recovery from injury led us to consider of the physiological rather than pathological role of myelin inhibitors. We found that experience-dependent cortical plasticity is gated by NgR-dependent mechanisms in the absence of injury. While this work has defined one pathway regulating adult CNS axonal sprouting, it has also framed crucial questions about NgR function that will be addressed in the second cycle of this project. In the proposed work, we will examine the anatomical, molecular and temporal specificity of NgR action in plasticity and regeneration. We will consider the cellular basis for NgR-gated brain plasticity. The current hypothesis is that NgR functions to "lock" neuronal elements into place and to prevent anatomical rearrangements. The molecular basis for NgR signal transduction will also be probed biochemically and genetically. Together, these studies should provide critical insights into the mechanism and extent of NgR contribution to axonal plasticity and regeneration in the adult CNS. Such data will inform our understanding of the stability of connectivity within the CNS and illuminate the possibility of harnessing this knowledge for therapeutic interventions.