Signal transduction in axon guidance

轴突引导中的信号转导

• 批准号: 8697148
• 负责人: John G Flanagan
• 金额: $ 39.84万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697148
• 关键词: Address; Adult; Area; Axon; Binding; Binding Proteins; Biological; Biology; Biomedical Research; Brain; Cell Surface Receptors; Cells; Complex; Cues; Development; Disease; Family; Floor; Goals; Health; High-Throughput Nucleotide Sequencing; In Vitro; Injury; Lead; Ligands; Logic; Mental Retardation; Messenger RNA; Modeling; Molecular; Natural regeneration; Nerve Regeneration; Neurons; Pattern; Phenotype; Process; Proteins; RNA; RNA-Binding Proteins; Recording of previous events; Regulation; Research; Research Design; Role; Signal Transduction; Spinal; Spinal Cord; Surveys; System; Techniques; Tissues; Translation Initiation; Translations; Up-Regulation; Work; axon growth; axon guidance; axon regeneration; base; extracellular; genome wide association study; in vivo; insight; interest; member; neurodevelopment; neuron development; novel; protein expression; receptor; repaired

DESCRIPTION (provided by applicant): The brain relies for its function on a complex pattern of axonal connections that are initially set up during development. The broad long-term goal of the project is to understand molecular signaling mechanisms that underly the process of pathfinding required for axons to grow toward their correct targets. The current proposal focuses particularly on RNA-based mechanisms, which have not been characterized extensively in the axon. Aim 1 builds on our recent work showing that the transmembrane axon guidance receptor DCC physically associates with translation initiation machinery, including eIFs and ribosomal subunits. This finding of functional and physical association of a cell surface receptor with the translation machinery leads to a generalizable model for extracellular regulation and localization of translation, based on a transmembrane translation regulation complex. Here we propose further studies to survey how general this phenomenon may be for different classes of receptor, focusing on receptors involved in neural development. Identification of this novel regulatory mechanism also raises interesting questions we will address regarding molecular components and interactions involved in the complex. Aim 2 extends our work which previously identified RNA-based mechanisms that can regulate protein expression within spinal commissural axons as they navigate past their well characterized intermediate guidance target, the floor plate of the spinal cord. We have identified RNA-binding proteins in the CPEB family that are involved in spinal commissural neuron pathfinding. We propose further studies of the functions of these RNA-binding proteins in axon guidance, using both in vitro and in vivo functional systems. We also propose studies of the downstream target mRNAs bound by these proteins, which will yield insight into their network of regulatory interactions. While our work focuses primarily on the basic biology of neuron development, it has broad implications for health research. Correct axon pathfinding is required for normal neural development, and RNA-based mechanisms are known to contribute to diseases such as mental retardation. Also, a major health problem is created by inability of adult neurons to regenerate, and ultimately the study of developmental pathfinding is likely to contribute to strategies for axon regeneration. More broadly, our work on the neuron provides a model to uncover fundamental principles with very general implications for biomedical research.

描述（由申请人提供）：大脑依赖其功能，以开发过程中最初设置的轴突连接的复杂模式。该项目的长期长期目标是了解轴突朝着正确靶标生长所需的路径联系过程的分子信号传导机制。当前的建议特别关注基于RNA的机制，这些机制在轴突中尚未广泛表征。 AIM 1建立在我们最近的工作基础上，表明跨膜轴突引导受体DCC与翻译起始机械（包括EIF和核糖体亚基）物理相关。基于跨膜翻译调节复合物，这种细胞表面受体与翻译机制的功能和物理关联的发现导致了一个可推广的模型，用于翻译的细胞外调节和定位。在这里，我们提出进一步的研究，以调查这种现象对不同类别的受体的一般性，重点是涉及神经发育的受体。这种新型调节机制的识别还提出了我们将解决有关该复合物中涉及的分子成分和相互作用的有趣问题。 AIM 2扩展了我们的工作，该工作以前鉴定出基于RNA的机制，这些机制可以调节脊柱连合轴突中的蛋白质表达，因为它们经过了表征良好的中间引导靶标，即脊髓的底板。我们已经鉴定出参与脊柱连合神经元探路的CPEB家族中的RNA结合蛋白。我们使用体外和体内功能系统都提出了这些RNA结合蛋白在轴突引导中的功能的进一步研究。我们还提出了对这些蛋白质约束的下游靶标mRNA的研究，这将洞悉其调节性相互作用网络。尽管我们的工作主要关注神经元发展的基本生物学，但它对健康研究具有广泛的影响。正常神经发育需要正确的轴突探路，并且已知基于RNA的机制会导致诸如智力低下的疾病。同样，由于成年神经元无法再生而产生了一个重大的健康问题，最终对发展性探索的研究可能会促进轴突再生策略。从更广泛的角度来看，我们在神经元上的工作提供了一个模型，以发现对生物医学研究的一般影响的基本原理。