Nogo Receptor Family: Novel Mechanisms to Inhibit Growth

Nogo 受体家族：抑制生长的新机制

• 批准号: 7116772
• 负责人: Roman Jeno Giger
• 金额: $ 34.27万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-02 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116772
• 关键词: axon; cell growth regulation; developmental neurobiology; gene targeting; genetically modified animals; glycoproteins; growth inhibitors; laboratory mouse; laboratory rat; ligands; nerve /myelin protein; nerve injury; nervous system regeneration; neural plasticity; neurogenesis; neuronal guidance; protein localization; protein protein interaction; protein structure function; receptor; receptor binding; receptor expression; syndecan; tissue /cell culture; transfection /expression vector

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.

描述（由申请人提供）：人类脊髓的创伤性损伤导致永久性瘫痪和其他严重的医疗并发症。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，切断的脊髓轴突恢复的失败主要不是由于固有的不能再生，而是由于中枢神经系统（CNS）环境对轴突生长高度难治。在脊髓损伤（SCI）动物模型中，当提供合适的环境时，受损的CNS轴突确实会恢复，长距离延伸过程并部分恢复功能。多种CNS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）和少突胶质细胞髓鞘糖蛋白（OMgp）。本研究的主要目的是深入了解髓鞘介导的轴突生长抑制的分子和细胞机制。详细了解轴突-神经胶质细胞相互作用的生物学是设计旨在降低成人CNS髓鞘的生长抑制屏障和促进CNS创伤性损伤后神经元修复的策略的先决条件。识别，一个新的家庭的受体蛋白的成员具有不同的结合特异性对建立髓鞘抑制剂的轴突生长是在我们的调查的核心。这项研究的主要目的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。为了在功能上表征该基因家族的成员，我们将设计重组病毒载体用于神经元中的功能获得研究。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。将评估仍然结合配体但不再具有信号传导轴突生长抑制的能力的突变的可溶性受体在体外促进髓鞘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，这个受体蛋白家族可能为CNS损伤的治疗干预设计提供新的分子手柄。