Cell-Cell Signaling in Development and Regeneration of Visual Connections

视觉连接发育和再生中的细胞间信号传导

基本信息

批准号：
8446418
负责人：
John G Flanagan
金额：
$ 44.16万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-09-30 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8446418
关键词：
Address Adult Affect Amyloid beta-Protein Amyloid beta-Protein Precursor Area Axon Behavior Binding Biological Biology Brain Carbohydrates Cell surface Cells Chondroitin Sulfate Proteoglycan Cues Development Dimerization Ephrins Eye Family Fc Receptor Funding Genes Goals Grant Heparan Sulfate Proteoglycan Heparitin Sulfate Injury Label Lead Ligands Link Mediating Molecular Natural regeneration Nerve Regeneration Neurons Optic Nerve Orphan Pathology Phosphoric Monoester Hydrolases Polysaccharides Process Protein Binding Protein Tyrosine Phosphatase Proteoglycan Proteolytic Processing Receptor Signaling Regulation Reporting Role Signal Transduction Signaling Molecule Structure System Therapeutic Vision Visual Visual system structure Work amyloid precursor protein processing axon growth axon guidance axon regeneration base contactin enzyme activity extracellular human PTPRT protein improved inhibitor/antagonist insight intercellular communication interest member novel novel therapeutics optic nerve regeneration receptor relating to nervous system response retinal axon retinotectal

Address Adult Affect Amyloid beta-Protein Amyloid beta-Protein Precursor Area Axon Behavior Binding Biological Biology Brain Carbohydrates Cell surface Cells Chondroitin Sulfate Proteoglycan Cues Development Dimerization Ephrins Eye Family Fc Receptor Funding Genes Goals Grant Heparan Sulfate Proteoglycan Heparitin Sulfate Injury Label Lead Ligands Link Mediating Molecular Natural regeneration Nerve Regeneration Neurons Optic Nerve Orphan Pathology Phosphoric Monoester Hydrolases Polysaccharides Process Protein Binding Protein Tyrosine Phosphatase Proteoglycan Proteolytic Processing Receptor Signaling Regulation Reporting Role Signal Transduction Signaling Molecule Structure System Therapeutic Vision Visual Visual system structure Work amyloid precursor protein processing axon growth axon guidance axon regeneration base contactin enzyme activity extracellular human PTPRT protein improved inhibitor/antagonist insight intercellular communication interest member novel novel therapeutics optic nerve regeneration receptor relating to nervous system response retinal axon retinotectal

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项目摘要

Correct functioning of the visual system requires a precise set of axonal connections from the eye to the brain. If these connections develop abnormally, or are later damaged by injury or degeneration, vision may be impaired or lost. The broad long-term objective of the project is to identify and characterize cell-cell signaling molecules involved in the development and regeneration of visual neuronal connections. In the adult visual system, like other parts of the CNS, axons show very limited capacity for regeneration. This is due, at least in part, to endogenous regeneration inhibitors, leading to great interest in strategies that might overcome the effect of these inhibitors, and thus promote plasticity and regeneration. Chondroitin sulfate proteoglycans (CSPGs) have long been known as an important class of inhibitors, but no corresponding receptor had been identified, limiting further molecular progress in this area. In recent work, we identified Protein Tyrosine Phosphatase sigma (PTPsigma) as a receptor for CSPGs, opening up new opportunities to study mechanisms in regeneration and potential therapeutic strategies. The role of this receptor in regeneration is confirmed by the effects of PTPsigma gene deficiency, which enhances regeneration, including of retinal axons in the optic nerve. In other recent work, we have shown that PTPsigma acts as a ligand- specific molecular switch, mediating not only CSPG inhibition but also heparan sulfate proteogylcan (HSPG) promotion of axon extension, providing a paradigm to understand opposing effects of CSPGs and HSPGs. Aim 1 has two inter-related goals: first, to better understand the basic biology of the interaction between PTPsigma and its proteoglycan ligands; and second, to explore compounds that can promote axon growth and optic nerve regeneration. Whereas Aim 1 focuses on extracellular interactions of PTPsigma, Aim 2 explores downstream transmembrane and intracellular signaling mechanisms. The prior work identifying HSPG and CSPG ligands for PTPsigma opens up new opportunities to understand the downstream mechanistic basis for the contrasting effects of these proteoglycans, and simultaneously to make new progress in understanding basic mechanisms of signaling by the receptor PTP family. Finally, Aim 3 proposes to continue studies of the Amyloid Precursor Protein (APP) and its binding partners expressed in the developing retinotectal system. While APP processing to beta-amyloid is known to have important roles in pathology, neither the normal developmental functions of APP nor the mechanisms that regulate its processing are yet well understood. Binding partners for APP have been identified which are prominently expressed in retinotectal development, and can affect retinal axon growth and APP processing. Further studies will provide improved understanding of these molecular interactions, with potential implications for development, degeneration and regeneration.

视觉系统的正确功能需要从眼睛到大脑的精确轴突连接。如果这些连接异常发展，或者后来因伤害或变性而损害，则视力可能是受损或丢失。该项目的广泛长期目标是识别和表征细胞电信信号传导参与视觉神经元连接的发展和再生的分子。在成人视觉系统中，与中枢神经系统的其他部分一样，轴突的再生能力非常有限。这至少部分归因于内源性再生抑制剂，导致对可能的策略产生极大的兴趣克服这些抑制剂的作用，从而促进可塑性和再生。硫酸软骨素蛋白聚糖（CSPG）长期以来一直被称为重要类抑制剂，但没有相应已经鉴定出受体，限制了该区域的进一步分子进展。在最近的工作中，我们确定了蛋白酪氨酸磷酸酶Sigma（Ptpsigma）作为CSPG的受体，为新的机会开放再生和潜在治疗策略中的研究机制。该受体在 Ptpsigma基因缺乏症的影响证实了再生，从而增强了再生，包括视神经中的视网膜轴突。在最近的其他工作中，我们表明ptpsigma充当配体特定的分子开关，不仅介导CSPG抑制作用，还会介导硫酸乙酰肝素proteogylcan（HSPG）促进轴突扩展，提供了一个范式，以了解CSPG和HSPG的相对影响。 AIM 1有两个相互关联的目标：首先，更好地了解 ptpsigma及其蛋白聚糖配体；其次，探索可以促进轴突生长和的化合物视神经再生。 AIM 1专注于Ptpsigma的细胞外相互作用，而AIM 2探索下游跨膜和细胞内信号传导机制。识别HSPG和用于Ptpsigma的CSPG配体为了解下游机理的新机会开辟了这些蛋白聚糖的对比效果，同时在理解方面取得了新的进步受体PTP家族信号传导的基本机制。最后，AIM 3建议继续研究淀粉样蛋白前体蛋白（APP）及其结合伴侣在发育中的视网膜直肠系统中表达。虽然已知对β-淀粉样蛋白的应用程序处理在病理学中具有重要作用，但既不是正常的 APP的发展功能或调节其处理的机制尚未得到充分理解。已经确定了在视网膜直肠发展中明显表达的应用程序的绑定伙伴，并可能影响视网膜轴突生长和应用程序处理。进一步的研究将提高人们对这些分子相互作用，对发展，变性和再生具有潜在的影响。