Between Slit and repulsion: Molecular mechanisms underlying Robo-mediated midline

狭缝与排斥之间：Robo 介导的中线的分子机制

基本信息

批准号：
8141972
负责人：
Rebecca Kent Chance
金额：
$ 4.18万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8141972
关键词：
Affect Attenuated Autistic Disorder Axon Behavior Biochemical Biochemistry Biological Biological Assay Biological Neural Networks Cell Culture Techniques Cell membrane Cells Cleaved cell Communication Complex Cues Data Development Disease Drosophila genus Dyslexia Endocytosis Event Exclusion Extracellular Domain Family Functional disorder Genetic Genetic Programming Goals Growth Cones Health Hereditary Disease Human Human Genetics In Vitro Individual Injury Instruction Knowledge Learning Ligands Light Linguistics Locomotion Mediating Metalloproteases Molecular Natural regeneration Nervous system structure Neuraxis Neurodegenerative Disorders Neurons Pattern Peptide Hydrolases Process Proteolysis Proteolytic Processing Receptor Activation Receptor Signaling Regulation Role Schizophrenia Series Shapes Signal Transduction Site Surface Syndrome Testing Therapeutic Therapeutic Intervention Transplantation Variant axon growth axon guidance behavior influence design extracellular gamma secretase gaze palsy horizontal gaze in vivo insight mutant receptor repaired research study response scoliosis spatiotemporal

项目摘要

DESCRIPTION (provided by applicant): Proper connectivity of the central nervous system allows for communication between hemispheres necessary for such diverse functions as locomotion and linguistic processing. A clear understanding of how an individual axon growth cone makes a guidance decision during development is necessary to learn how reproducible connectivity patterns are accomplished in normal development. Knowledge as to how axon guidance receptors convert extracellular cues into a guidance choice will be essential to serve the long-term goal of guiding rewiring in developmental disease, neurodegenerative disease or injury states. This proposal is designed to provide mechanistic insight into the how the regulation of signaling of one axon guidance receptor, Roundabout (Robo) affects its repulsive guidance instruction. Determining whether and how the spatiotemporal profile of activated Robo affects growth cone guidance is a largely unexplored topic and may provide insight into general mechanisms of guidance receptor regulation. The proposed experiments use Drosophila genetics, biochemistry, and cell culture approaches to test the hypothesis that ligand-dependent internalization of Robo, by proteolysis and endocytosis, regulates the spatiotemporal dynamics of signaling within a growth cone during repulsive guidance. Knowledge of the mechanism by which an activated receptor informs wiring decisions will provide insight into optimal points of therapeutic intervention in developmental diseases of miswiring and repair following injury or neurodegenerative disorder.

描述（由申请人提供）：中枢神经系统的适当连通性允许在运动和语言处理等多种功能所需的半球之间进行通信。对单个轴突生长锥如何在开发过程中做出指导决策的清晰了解，以了解如何在正常开发中完成可再现的连通性模式。关于轴突引导受体如何将细胞外提示转换为指导选择的知识对于指导在发育疾病，神经退行性疾病或损伤状态的长期目标至关重要。该建议旨在提供机械洞察力，以了解一个轴突指导受体的信号传导如何影响其排斥指导的指导。确定活化机器人的时空谱以及如何影响生长锥引导是一个未开发的主题，并且可能会洞悉指导受体调节的一般机制。提出的实验使用果蝇遗传学，生物化学和细胞培养方法来检验以下假说，即通过蛋白水解和内吞作用，可以调节在抑制性指导期间，通过蛋白水解和内吞作用来调节生长锥体内信号的时空动态。了解激活受体告知接线决策的机制，将洞悉受伤或神经退行性疾病后错误和修复的发育疾病的最佳治疗干预点。