Nogo Receptor Family: Novel Mechanisms to Inhibit Growth

描述(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位之间失去神经元连接的结果。然而，切断的脊髓轴突未能恢复，主要不是由于固有的再生能力，而是中枢神经系统(CNS)环境对轴突生长高度抵抗的结果。在脊髓损伤(SCI)动物模型中，在适当的环境下，受损的CNS轴突确实可以恢复，延长突起的距离，并部分恢复功能。多种中枢神经系统髓鞘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、髓鞘相关糖蛋白(MAG)和少突胶质细胞髓磷脂糖蛋白(OMGp)。本研究的主要目的是深入了解髓鞘介导的抑制轴突生长的分子和细胞机制。对轴突-神经胶质细胞相互作用生物学的详细了解是设计旨在降低成年中枢神经系统髓鞘生长抑制屏障和促进中枢神经系统损伤后神经元修复的策略的先决条件。一个新的受体蛋白家族的鉴定是我们研究的核心，该家族由与已建立的轴突生长的髓鞘抑制物具有不同结合特异性的成员组成。这项拟议研究的一个主要目标是确定这些受体在中枢神经系统髓鞘抑制剂的神经元反应中的作用。为了确定该基因家族成员的功能特征，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的研究。在一种平行的方法中，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与配体结合，但不再具有发出轴突生长抑制信号的能力，将在体外评估它们在髓鞘基质上促进轴突生长的潜力。将我们的生化方法与体外轴突生长分析和体内功能研究相结合，将为阐明新型受体-配体相互作用在抑制轴突生长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设计中枢神经系统损伤的治疗干预提供新的分子手柄。

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.