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

• 批准号: 8002947
• 负责人: Rebecca Kent Chance
• 金额: $ 4.14万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/8002947
• 关键词: Affect; Autistic Disorder; Biochemistry; Cell Culture Techniques; Communication; Cues; Development; Disease; Drosophila genus; Dyslexia; Endocytosis; Functional disorder; Genetic; Genetic Programming; Goals; Growth Cones; Health; Hereditary Disease; Human; Human Genetics; Individual; Injury; Instruction; Knowledge; Learning; Ligands; Linguistics; Locomotion; Mediating; Molecular; Natural regeneration; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Pattern; Process; Proteolysis; Regulation; Role; Schizophrenia; Shapes; Signal Transduction; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Transplantation; Variant; axon growth; axon guidance; design; extracellular; gaze palsy; horizontal gaze; insight; public health relevance; receptor; repaired; research study; scoliosis; spatiotemporal

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. PUBLIC HEALTH RELEVANCE: This proposal is designed to further our understanding of the genetic programs regulating proper wiring of nervous systems during development by uncovering the factors necessary for regulating the axon guidance receptor Roundabout (Robo). Understanding the mechanisms controlling Robo signaling in Drosophila growth cones will provide insight into human health and disease. Robo's role in shaping nervous system connectivity is conserved in humans; understanding its normal mode of action in development will help us to develop therapeutics for a human genetic disorder of aberrant nervous system wiring- Horizontal Gaze Palsy and Progressive Scoliosis- and will help us understand the pathophysiology of common-disease common-variant syndromes such as autism, schizophrenia, dyslexia and periventricular nodular heterotopia. Learning how normal growth cones navigate during development will also be essential to guiding rewiring in regeneration and transplantation therapeutics.

描述（由申请人提供）：中枢神经系统的适当连接允许半球之间的通信，这些通信对于运动和语言处理等多种功能是必要的。清楚地了解单个轴突生长锥在发育过程中如何做出指导性决定，对于了解正常发育中如何实现可重复的连接模式是必要的。关于轴突引导受体如何将细胞外线索转化为引导选择的知识对于指导发育性疾病、神经退行性疾病或损伤状态中的重新布线的长期目标至关重要。 这个建议的目的是提供机制的洞察如何调节轴突导向受体，回旋处（机器人）的信号影响其排斥性的指导指令。确定激活的Robo的时空分布是否以及如何影响生长锥的指导是一个很大程度上未探索的主题，并可能提供指导受体调节的一般机制的见解。拟议的实验使用果蝇遗传学，生物化学和细胞培养的方法来测试的假设，配体依赖的内化的机器人，通过蛋白水解和内吞作用，调节时空动态的信号在排斥指导的生长锥。激活的受体告知布线决策的机制的知识将提供对在损伤或神经退行性疾病后的布线错误和修复的发育疾病中的治疗干预的最佳点的洞察。 公共卫生关系：该提案旨在通过揭示调节轴突导向受体Roundabout（Robo）所需的因素，进一步了解发育过程中调节神经系统正确布线的遗传程序。了解果蝇生长锥中控制Robo信号的机制将为人类健康和疾病提供深入了解。Robo在塑造神经系统连接方面的作用在人类中是保守的;了解其在发育中的正常作用模式将有助于我们开发治疗异常神经系统布线的人类遗传性疾病-水平凝视麻痹和进行性脊柱侧凸-并将帮助我们了解常见疾病常见变异综合征的病理生理学，如自闭症，精神分裂症，阅读障碍和脑室周围结节性异位。了解正常生长锥在发育过程中如何导航，对于指导再生和移植治疗中的重新布线也至关重要。