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; 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通过通过神经元表面受体Ngr在髓磷脂表面作用，抑制神经突的生长。针对NoGo-NGR途径的疗法在治疗脊髓损伤和其他中枢神经系统疾病方面有希望。但是，关于Nogo在未受伤的细胞中的功能，尚不清楚。 Nogo是Reticulon家族的成员，这是一套保守的内质网（ER）相关蛋白，具有不明确的功能。 Nogo表达的大部分是细胞内而不是表面相关的。另外，Nogo在神经元以及少突胶质细胞中都显着表达。这些事实除了抑制轴突生长外，Nogo发挥了其他作用。我们获得了数据，表明Nogo同工型调节细胞内流量。此外，Nogo水平会影响轴突运输的专门神经元运输途径。 Nogo可以通过RAB家族的小型GTPases调解其对交通的影响。此外，Nogo可能会影响其自身受体的贩运，从而创建一种以前尚未探索的NGR调节形式。最后，Nogo可以在运动神经元疾病的背景下增强神经元存活。更好地理解这些角色至关重要，因为正在开发疗法以阻止中枢神经系统损伤的NOGO途径。该提案的目的是进一步探索Nogo使用各种细胞成像和生化技术参与细胞内贩运的机制。 Nogo对轴突转运和突触囊泡回收的专业神经元运输途径的影响将通过来自野生型和Nogo-Nogo-Knockout小鼠的神经元的现场细胞成像研究来探索。这些研究将在Stephen M. Strittmatter博士的指导下进行，该领域是神经创造和轴突信号转导领域的领导者。他和他非常资金的实验室为开发成功的神经科学研究所需技术的专业知识提供了最佳环境。此外，耶鲁大学神经病学系已致力于通过限制临床责任来促进申请人的发展，以使至少85％的努力致力于研究，并通过将开放的实验室空间作为申请人过渡到本提案期间运行独立实验室。对Nogo途径的作用在阻断大脑中受伤的神经和脊髓再生方面的作用进行了深入研究。但是，该提议表明，Nogo还起着重要的作用，可能有助于神经的功能。洞悉这些角色将揭示Nogo参与肌萎缩性侧面硬化症等疾病，并将有助于指导在脊髓损伤和其他破坏性中枢神经系统疾病的情况下，有助于指导更安全的疗法以抑制Nogo途径。