Signal transduction in axon guidance

轴突引导中的信号转导

• 批准号: 8291236
• 负责人: John G Flanagan
• 金额: $ 40.24万
• 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/8291236
• 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; 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）：大脑的功能依赖于在发育过程中最初建立的复杂的轴突连接模式。该项目广泛的长期目标是了解轴突向正确目标生长所需的寻路过程的分子信号传导机制。目前的建议特别关注基于RNA的机制，这在轴突中还没有得到广泛的表征。目的1建立在我们最近的工作表明，跨膜轴突导向受体DCC物理关联的翻译起始机制，包括eIF和核糖体亚基。这一发现的功能和物理协会的细胞表面受体与翻译机制导致一个可推广的模型，细胞外的调节和本地化的翻译，基于跨膜翻译调节复合物。在这里，我们提出了进一步的研究，调查如何普遍这种现象可能是不同类别的受体，集中在受体参与神经发育。这种新的监管机制的鉴定也提出了有趣的问题，我们将解决有关复杂的分子组成和相互作用。目的2扩展了我们先前确定的基于RNA的机制的工作，该机制可以调节脊髓连合轴突内的蛋白质表达，因为它们通过其良好表征的中间引导靶点，脊髓底板。我们已经确定了CPEB家族中参与脊髓连合神经元寻路的RNA结合蛋白。我们建议进一步研究这些RNA结合蛋白在轴突导向中的功能，使用体外和体内功能系统。我们还建议研究这些蛋白质结合的下游靶mRNA，这将深入了解它们的调控相互作用网络。虽然我们的工作主要集中在神经元发育的基础生物学上，但它对健康研究具有广泛的影响。正确的轴突寻路是正常神经发育所必需的，并且已知基于RNA的机制有助于诸如智力迟钝等疾病。此外，一个主要的健康问题是由成年神经元无法再生造成的，最终对发育寻路的研究可能有助于轴突再生的策略。更广泛地说，我们对神经元的研究提供了一个模型，可以揭示对生物医学研究具有普遍意义的基本原理。