Nogo Receptor Family: Novel Mechanisms to Inhibit Growth

描述（由申请人提供）：人类脊髓的创伤性损伤会导致永久性瘫痪和其他严重的医学并发症。瘫痪是大脑和脊髓运动单元之间失去神经元连接的结果。然而，切断的脊髓轴突恢复失败，主要不是由于内在的无法再生，而是中枢神经系统（CNS）环境对轴突生长的高度难阻性的结果。在脊髓损伤（SCI）动物模型中，当提供适当的环境时，受损的中枢神经系统轴突确实会恢复，延长过程的距离并部分恢复功能。多种中枢神经系统髓磷脂成分被认为直接导致受损脊髓轴突的再生失败，包括称为Nogo的蛋白质，髓磷脂相关糖蛋白（MAG）和少突胶质-髓磷脂糖蛋白（OMgp）。本研究的主要目的是深入了解髓磷脂介导的轴突生长抑制的分子和细胞机制。详细了解轴突-胶质细胞相互作用的生物学是设计旨在降低成人中枢神经系统髓鞘生长抑制屏障和促进中枢神经系统创伤性损伤后神经元修复策略的先决条件。鉴定一个新的受体蛋白家族，其成员对轴突生长的髓磷脂抑制剂具有不同的结合特异性，是我们研究的核心。本研究的主要目的是确定这些受体在中枢神经系统髓磷脂抑制剂的神经元反应中的作用。为了功能表征该基因家族成员，我们将设计重组病毒载体用于神经元的功能获得研究。小鼠遗传学将用于体内功能丧失研究。在平行的方法中，我们将开发具有拮抗功能的突变受体。突变的可溶性受体仍然结合配体，但不再具有信号轴突生长抑制的能力，将评估其在体外促进髓磷脂底物上轴突生长的潜力。将我们的生化方法与体外神经突生长测定和体内功能研究相结合，将为阐明新型受体-配体相互作用在神经突生长抑制中所起的作用提供强有力的基础。总之，这一受体蛋白家族可能为中枢神经系统损伤的治疗干预设计提供新的分子处理。

DESCRIPTION (provided by applicant): Traumatic injury of the spinal cord in humans leads to permanent paralysis and other serious medical complications. Paralysis is a result of lost neuronal connectivity between the brain and spinal cord motor units. The failure of severed spinal axons to recover, however, is not primarily due to an intrinsic inability to regenerate, but is a result of the central nervous system (CNS) environment that is highly refractory to axonal growth. When provided with a suitable environment, injured CNS axons do recover, extending processes over long distances and partially restoring function in animal models of spinal cord injury (SCI). Multiple CNS myelin constituents are thought to directly contribute to the regenerative failure of damaged spinal axons, including proteins called Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp). The main objective of this study is to gain insights into the molecular and cellular mechanisms of myelin-mediated inhibition of axonal growth. A detailed understanding of the biology of axon-glia interaction is a prerequisite to devising strategies aimed at lowering the growth inhibitory barrier of adult CNS myelin and to promote neuronal repair following traumatic injury of the CNS. The identification, of a novel family of receptor proteins comprised of members with distinct binding specificities toward established myelin inhibitors of axonal growth is at the heart of our investigations. A major goal of the proposed study is to define the role of these receptors in neuronal responses to CNS myelin inhibitors. To functionally characterize members of this gene family, we will engineer recombinant viral vectors for gain-of-function studies in neurons. Mouse genetics will be used for loss-of-function studies in vivo. In a parallel approach, we will develop mutated receptors with antagonistic function. Mutated soluble receptors that still bind ligand but no longer possess the ability to signal axonal growth inhibition will be assessed for their potential to promote axonal growth on myelin substrate in vitro. Coupling our biochemical approaches with in vitro neurite outgrowth assays and in vivo functional studies will provide a strong basis to elucidate the role played by novel receptor-ligand interactions in neurite outgrowth inhibition. Together, this family of receptor proteins may provide new molecular handles for the design of therapeutic interventions for CNS injuries.