A chemical approach to elucidating the structure-function relationships of chondronitin sulfate glycosaminoglycans

阐明硫酸软骨素糖胺聚糖结构与功能关系的化学方法

• 批准号: 8965476
• 负责人: Linda C Hsieh-Wilson
• 金额: $ 53.63万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8965476
• 关键词: Aging; Antibodies; Axon; Biological Process; Biology; Brain; Cell Surface Receptors; Chemicals; Chondroitin Sulfate A; Chondroitin Sulfates; Cicatrix; Complex; Development; Disease; Eph Family Receptors; Ephrins; Event; Family; Genes; Genetic; Global Change; Glycosaminoglycans; Goals; Grant; Health; Immunoglobulin Fragments; Injury; Inorganic Sulfates; Knockout Mice; Lead; Ligands; Malignant Neoplasms; Mediating; Methods; Molecular; Monoclonal Antibodies; Natural regeneration; Nerve Regeneration; Nervous system structure; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Neuropilin-1; Organic Chemistry; Pathway interactions; Pattern; Play; Polymers; Polysaccharides; Process; Proteins; Receptor Activation; Regulation; Research; Role; Semaphorin-3A; Signal Pathway; Signal Transduction; Signaling Protein; Spinal Cord; Spinal cord injury; Structure; Structure-Activity Relationship; Synaptic plasticity; System; Unspecified or Sulfate Ion Sulfates; Viral; Visual Cortex; Work; axon regeneration; central nervous system injury; chondroitin sulfate glycosaminoglycan; in vivo; inhibitor/antagonist; insight; mimetics; neural circuit; neurodevelopment; novel; novel strategies; novel therapeutic intervention; novel therapeutics; optic nerve regeneration; plexin; polysulfated glycosaminoglycan; programs; receptor; repaired; response; small molecule; sulfation; sulfotransferase; tool

 DESCRIPTION (provided by applicant): This project will focus on chondroitin sulfate glycosaminoglycans (CS GAGs), a class of polysaccharides that play important roles in development, viral invasion, cancer, and spinal cord injury. CS GAGs display diverse sulfation patterns that are spatiotemporally regulated in vivo. However, efforts to identify functions for specific sulfation motifs have been hampered by the structural complexity of CS and a lack of tools. In this grant, we will combine the power of both organic chemistry and biology to overcome these challenges and identify novel functions for specific motifs in the nervous system. The broad objectives of this program are to: (1) advance a fundamental understanding of the structure-function relationships of CS GAGs, (2) understand the roles of CS GAGs in neuroplasticity and regeneration, and (3) develop new approaches to study and manipulate GAG-mediated biological processes, with the long-term goal of stimulating synaptic plasticity and neuronal repair. In the last granting period, we developed a set of chemical tools to study specific sulfation motifs and discovered that a particular motif, CS-E, inhibits axon regeneration after spinal cord injury. Blocking the CS-E motif using an anti-CS-E antibody stimulated axon regeneration in vivo. Moreover, we found that this same motif repels axons and plays a critical role in neural circuit formation during brain development. An important observation from this work was that the activity of CS-E required its interaction with cell-surface receptors and activation of specific inhibitory signaling pathways in neurons. In the present grant, we will develop new approaches to modulate the interactions of CS-E with neuronal receptors, including the viral-mediated delivery of single-chain anti-CS-E antibodies, small- molecule sulfotransferase inhibitors, and glycopolymer mimetics (Aim 1). We will study how CS-E regulates protein signaling complexes, with a particular focus on semaphorin-3A/neuropilin-1/plexin A (Sema3A/Nrp1/PlxnA) and ephrin/Eph receptor (Efn/Eph) complexes (Aims 2a and 3a). Finally, we will investigate the ability of the agents developed in Aim 1 to promote neuroplasticity in the visual cortex (Aims 2b,c) and axon regeneration after spinal cord injury (Aim 3b). These studies are expected to provide new chemical tools to advance an understanding of GAGs and fundamentally change how CS GAGs are viewed - from being static, passive molecules to ligands that actively regulate important signaling pathways. Finally, if successful, the agents developed in Aim 1 could lead to novel therapeutic strategies for stimulating neuronal plasticity and repair in the case of aging, injury, and disease.

 描述（由适用提供）：该项目将重点关注硫酸软骨糖胺聚糖（CS GAGS），这是一类在发育，病毒入侵，癌症和脊髓损伤中起重要作用的多糖。 CS插科打s显示了在体内在空间调节的潜水硫酸化模式。但是，CS的结构复杂性和缺乏工具的结构复杂性阻碍了确定特定硫酸基序的功能的努力。在这笔赠款中，我们将结合有机化学和生物学的力量来克服这些挑战，并确定神经系统中特定基序的新功能。该计划的广泛目标是：（1）对CS GAGS的结构功能关系进行基本了解，（2）了解CS GAG在神经可塑性和再生中的作用，（3）开发了研究和操纵GAG介导的生物学过程的新方法，并具有长期的刺激性塑料和Neuronaptal synapteric synapter synataptic synapter synapteral and Neurronatial and Neurronatial and Neurronatial and Neurronatial and Neurony。在最后的给予期间，我们开发了一组化学工具来研究特定的硫酸化基序，并发现特定的基序CS-E抑制脊髓损伤后轴突再生。使用抗CS-E抗体刺激体内轴突再生来阻止CS-E基序。此外，我们发现相同的基序排斥轴突，并在大脑发育过程中在神经元电路形成中起关键作用。这项工作的一个重要观察结果是，CS-E的活性需要与细胞表面受体的相互作用以及神经元中特定抑制信号通路的激活。在目前的赠款中，我们将开发新的方法来调节CS-E与神经元受体的相互作用，包括病毒介导的单链抗CS-E抗体的递送，小分子磺基转移酶抑制剂，以及糖聚聚物的小分子抑制剂和类似物的模拟物（AIM 1）。我们将研究CS-E如何调节蛋白质信号复合物，特别关注Semaphorin-3A/Neuropilin-1/Plexin-1/Plexin A（SEMA3A/NRP1/PLXNA）和EPHRIN/EPH受体（EFN/EPH）复合物（AIMS 2A和3A）。最后，我们将研究AIM 1中发展的代理在脊髓损伤后（AIMS 2B，C）和轴突再生中促进神经可塑性的能力（AIM 3B）。预计这些研究将提供新的化学工具，以提高人们对插科打g的了解，并从根本上改变观察CS插科打的方式 - 从是静态的，被动分子到积极调节重要信号通路的配体。最后，如果成功的话，AIM 1中开发的试剂可能会导致新的热策略在衰老，损伤和疾病的情况下刺激神经元可塑性和修复。