Nogo Receptor Family: Novel Mechanisms to Inhibit Growth

Nogo 受体家族：抑制生长的新机制

基本信息

批准号：
7236754
负责人：
Roman Jeno Giger
金额：
$ 4.89万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-02 至 2008-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7236754
关键词：
Address Adult Affinity Animal Model Attenuated Axon Binding Biochemical Biological Assay Biology Brain C-terminal Cell Surface Receptors Cell membrane Cells Cellular Morphology Classification Complex Coupling Cytoplasmic Tail Docking Drug or chemical Tissue Distribution Ectopic Expression Embryo Engineering Environment Failure Family Family member Gene Family Gene Targeting Generations Genetic Glycoproteins Glycosaminoglycans Goals Growth Heart Heparan Sulfate Proteoglycan Human Immune Sera Immunoprecipitation In Vitro Injury Investigation Knockout Mice Laboratories Ligand Binding Ligand Binding Domain Ligands Link Maps Mediating Mediator of activation protein Molecular Motor Mus Mutate Myelin Myelin Associated Glycoprotein NGFR Protein Natural regeneration Nature Nervous System Trauma Nervous system structure Neuraxis Neurites Neuroglia Neuronal Plasticity Neurons Organism Paralysed Pattern Phenotype Principal Investigator Process Property Proteins Rattus Reagent Receptor Gene Receptor Signaling Recombinants Refractory Role Role playing therapy Sequence Homology Series Signal Pathway Signal Transduction Site Specificity Spinal Spinal Cord Spinal cord injury Stress Testing Therapeutic Intervention Thinking Viral Vector axon growth axon regeneration base central nervous system injury design functional restoration gain of function glycosaminoglycan receptor granule cell in vivo inhibitor/antagonist injured insight loss of function medical complication member neuronal cell body novel oligodendrocyte-myelin glycoprotein postnatal preference programs promoter receptor receptor function repaired research study response syndecan syndecan 3 transcriptional coactivator p75

项目摘要

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麻痹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神经元连通性丧失的结果。但是，切断的脊柱轴突无法恢复，这并不主要是由于内在无法再生的原因，而是中枢神经系统（CNS）环境对轴突生长高度难治性的结果。当提供合适的环境时，受伤的CNS轴突确实会恢复，从而在长距离上扩展过程，并在脊髓损伤动物模型（SCI）中部分恢复功能。人们认为多种CNS髓磷脂成分直接导致受损的脊柱轴突的再生衰竭，包括称为Nogo，与髓磷脂相关的糖蛋白（MAG）和少突胶质细胞蛋白酶糖蛋白糖蛋白糖蛋白（OMGP）的蛋白质。这项研究的主要目的是了解髓磷脂介导的轴突生长抑制的分子和细胞机制。对Axon-GLIA相互作用的生物学的详细理解是制定旨在降低成年CNS髓磷脂生长抑制障碍并在CNS创伤后促进神经元修复的策略的先决条件。我们研究的新型受体蛋白家族的鉴定是对轴突生长的建立髓磷脂抑制剂具有独特结合特异性的组成的核心。该研究的主要目的是定义这些受体在对CNS髓磷脂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向量，以在神经元中的功能性研究。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。仍将结合配体但不再具有信号轴突生长抑制的能力的突变的可溶性受体将被评估，以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法和体内功能研究结合在一起，将提供有力的基础，以阐明新型受体 - 配体相互作用在神经突生长抑制中的作用。总之，这种受体蛋白家族可能会为中枢神经系统损伤的治疗干预提供新的分子手柄。