Nogo's role in intracellular trafficking

Nogo 在细胞内运输中的作用

• 批准号: 7626455
• 负责人: NOAM Y. HAREL
• 金额: $ 15.57万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7626455
• 关键词: Affect; Amyotrophic Lateral Sclerosis; Axon; Biochemical; Brain; Cells; Central Nervous System Diseases; Clinical; Commit; Data; Development; Disease; Dissociation; Dyes; Endocytosis; Endoplasmic Reticulum; Endosomes; Exocytosis; Family; Fostering; Funding; Genotype; Golgi Apparatus; Immunoprecipitation; In Vitro; Kinetics; Knockout Mice; Knowledge; Laboratories; Life; Ligands; Light; Measures; Mediating; Membrane; Mentorship; Molecular; Monomeric GTP-Binding Proteins; Motor Neuron Disease; Myelin; Natural regeneration; Nerve; Neurites; Neurodegenerative Disorders; Neurology; Neurons; Nucleotides; Oligodendroglia; Pathway interactions; Physiologic pulse; Plasmids; Play; Protein Isoforms; Proteins; Recycling; Regulation; Research; Research Design; Research Personnel; Retrieval; Role; Running; Signal Transduction; Sorting - Cell Movement; Spinal Cord; Spinal cord injury; Stroke; Surface; Synapses; Synaptic Vesicles; Techniques; Variant; Vesicle; axon growth; cell motility; cell type; cellular imaging; central nervous system injury; extracellular; inhibitor/antagonist; injured; insight; member; mouse model; neuronal survival; programs; rab GTP-Binding Proteins; receptor; trafficking

DESCRIPTION (provided by applicant): Nogo inhibits neurite outgrowth by acting at the myelin surface through a neuronal surface receptor, NgR. Therapies targeting the Nogo-NgR pathway show promise in the treatment of spinal cord injury and other central nervous system diseases. However, much remains unknown regarding Nogo's function in uninjured cells. Nogo is a member of the Reticulon family, a conserved set of endoplasmic reticulum (ER)-associated proteins with unclear functions. The bulk of Nogo expression is intracellular rather than surface-associated. Additionally, Nogo is prominently expressed in neurons as well as in oligodendrocytes. These facts argue for other roles played by Nogo besides inhibiting axon growth. We have obtained data suggesting that Nogo isoforms regulate intracellular traffic. Furthermore, Nogo levels affect the specialized neuronal trafficking pathway of axon transport. Nogo may mediate its effects on traffic through small GTPases of the Rab family. Additionally, Nogo may affect trafficking of its own receptor, thereby creating a form of NgR regulation that has not previously been explored. Finally, Nogo may enhance neuronal survival in the context of motor neuron disease. Better understanding of these roles is crucial as therapies are being developed to block the Nogo pathway in the treatment of central nervous system injury. The Aims of this proposal are to further explore the mechanisms of Nogo's involvement in intracellular trafficking using a variety of cell imaging and biochemical techniques. Nogo's effects on the specialized neuronal trafficking pathways of axon transport and synaptic vesicle recycling will be explored with live cell imaging studies in neurons from wild type and Nogo-knockout mice. These studies will be performed under the mentorship of Dr. Stephen M. Strittmatter, a leader in the field of neuroregeneration and axonal signal transduction. He and his extremely well-funded laboratory provide the optimal setting for developing expertise in the techniques required for successful neuroscientific research. Furthermore, Yale's Department of Neurology has committed to fostering the applicant's development by limiting clinical responsibilities to allow at least 85% effort devoted to research, and by keeping open laboratory space available as the applicant transitions to running an independent laboratory during the period of this proposal. The Nogo pathway is intensely studied for its role in blocking injured nerves in the brain and spinal cord from regenerating. However, this proposal shows that Nogo also plays important roles that may help uninjured nerves function. Insight into these roles will shed light on Nogo's involvement in diseases like amyotrophic lateral sclerosis, and will help guide the development of safer therapies to inhibit the Nogo pathway in the context of spinal cord injury and other devastating central nervous system diseases.

描述（由申请人提供）：Nogo 通过神经元表面受体 NgR 作用于髓磷脂表面来抑制神经突生长。针对 Nogo-NgR 通路的疗法在治疗脊髓损伤和其他中枢神经系统疾病方面显示出前景。然而，关于 Nogo 在未受伤细胞中的功能，仍有许多未知之处。 Nogo 是 Reticulon 家族的成员，该家族是一组保守的内质网 (ER) 相关蛋白，功能尚不清楚。 Nogo 的大部分表达是在细胞内而不是表面相关的。此外，Nogo 在神经元和少突胶质细胞中显着表达。这些事实证明了 Nogo 除了抑制轴突生长之外还发挥着其他作用。我们获得的数据表明 Nogo 同种型调节细胞内交通。此外，Nogo 水平影响轴突运输的专门神经元运输途径。 Nogo 可能通过 Rab 家族的小型 GTPases 来调节其对流量的影响。此外，Nogo 可能会影响其自身受体的运输，从而产生一种以前从未探索过的 NgR 调节形式。最后，Nogo 可能会增强运动神经元疾病中神经元的存活率。更好地理解这些作用至关重要，因为正在开发阻断 Nogo 通路治疗中枢神经系统损伤的疗法。该提案的目的是利用各种细胞成像和生化技术进一步探讨 Nogo 参与细胞内运输的机制。将通过对野生型和 Nogo 敲除小鼠的神经元进行活细胞成像研究，探讨 Nogo 对轴突运输和突触小泡回收的专门神经元运输途径的影响。这些研究将在神经再生和轴突信号转导领域的领导者 Stephen M. Strittmatter 博士的指导下进行。他和他资金雄厚的实验室为发展成功的神经科学研究所需的技术专业知识提供了最佳环境。此外，耶鲁大学神经病学系致力于通过限制临床责任以允许至少 85% 的精力投入研究来促进申请人的发展，并在申请人在此提案期间过渡到运行独立实验室时保持开放的实验室空间。 Nogo 通路因其在阻止大脑和脊髓受损神经再生方面的作用而受到深入研究。然而，这一提议表明，Nogo 也发挥着重要作用，可能有助于未受伤的神经发挥功能。对这些作用的深入了解将揭示 Nogo 与肌萎缩侧索硬化症等疾病的关系，并将有助于指导开发更安全的疗法，以在脊髓损伤和其他破坏性中枢神经系统疾病的情况下抑制 Nogo 通路。