SOCS3 and optic nerve regeneration

SOCS3 和视神经再生

基本信息

批准号：
8258717
负责人：
ZHIGANG HE
金额：
$ 43.5万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8258717
关键词：
Address Adult Axon Circadian Rhythms Cytokine Inducible SH2-Containing Protein Data Disease Eye diseases Failure Foundations Genes Glaucoma Health Inherited Knock-out Knockout Mice Knowledge Lead Light Mediating Mediator of activation protein Modeling Molecular Target Mus Natural regeneration Neurons Neuropathy Optic Nerve Optic Nerve Injuries Optics PTEN gene Pathway interactions Patients Pilot Projects Protein Tyrosine Phosphatase Recovery of Function Research Retinal Retinal Ganglion Cells STAT3 gene Side Signal Pathway Signal Transduction Sirolimus Site Synapses TSC1 gene Therapeutic Transgenic Mice Translating axon growth axon regeneration gain of function human FRAP1 protein inhibitor/antagonist injured insight loss of function mTOR Inhibitor mouse model mutant neurodevelopment neuronal survival novel therapeutics optic nerve regeneration regenerative repaired research study src Homology Region 2 Domain suprachiasmatic nucleus

项目摘要

DESCRIPTION (provided by applicant): Optic nerve damage and regeneration failure are major features of glaucoma, inherited and traumatic optic neuropathies, and other blinding diseases. Developing strategies to promote anatomical regeneration and functional re-connection of injured optic nerve has been a long-standing challenge. By using an intraorbital optic nerve injury model in adult mice, we discovered that conditional deletion of SOCS3 and PTEN/TSC1 in RGCs promotes significant neuronal survival and axon regeneration. Our further studies suggested mTOR as a critical mediator of axon regeneration after PTEN/TSC1 deletion, likely by controlling the ability of injured neurons to synthesize materials for axon growth. On the other side, our data suggested that axon regeneration after SOCS3 deletion depends on gp130 signaling. In this proposal, we will address the following questions: First, what is the effector of SOCS deletion in promoting neuronal survival and axon regeneration and whether SOCS3 is the only key negative regulator? Second, do SOCS3-dependent and PTEN/TSC1-dependent pathways interact? Third, are regenerating axons able to find their pathway and mediate functional recovery? We expect that these experiments will provide important insights into the understanding the mechanisms of optic axon regeneration and the development of neural repair therapeutics. PUBLIC HEALTH RELEVANCE: Optic nerve damage and regeneration failure are major features of glaucoma, inherited and traumatic optic neuropathies, and other blinding diseases. Developing strategies to promote anatomical regeneration and functional re-connection of injured optic nerve has been a long-standing challenge. By AAV-Cre-assisted conditional knockout of floxed mouse genes, we recently made an exciting discovery that deletion of SOCS3 (suppressor of cytokine signaling 3) in adult retinal ganglion cells (RGCs) enables robust long-distance axon regeneration after intraorbital optic nerve injuries, revealing a potentially important signaling pathway in regulating axon regenerative ability of mature CNS neurons. The objectives of this proposed study are two-folds: to determine the underlying mechanisms permitting axon regeneration in SOCS3-deleted neurons and to assess whether the regenerating axons could find the normal projection pathway and re-form synaptic connections with their central targets.

描述（由申请人提供）：视神经损伤和再生失败是青光眼，遗传和创伤性神经病以及其他盲目疾病的主要特征。制定促进解剖学再生和功能重新连接受伤的视神经的策略一直是一个长期的挑战。通过在成年小鼠中使用眶内视神经损伤模型，我们发现RGC中SOCS3和PTEN/TSC1的条件缺失可促进明显的神经元存活和轴突再生。我们的进一步研究表明，MTOR是PTEN/TSC1缺失后轴突再生的关键介体，可能是通过控制受伤的神经元合成材料以实现轴突生长的能力。另一方面，我们的数据表明SOCS3缺失后的轴突再生取决于GP130信号传导。在该提案中，我们将解决以下问题：首先，SOC删除在促进神经元生存和轴突再生以及SOCS3是否是唯一的关键负面调节器中的效应子？其次，依赖SOCS3和PTEN/TSC1依赖性途径是否相互作用？第三，再生轴突是否能够找到其途径并介导功能恢复？我们预计这些实验将为理解视轴突再生的机制和神经修复治疗剂的发展提供重要的见解。公共卫生相关性：视神经损伤和再生失败是青光眼，遗传和创伤性神经病以及其他盲目疾病的主要特征。制定促进解剖学再生和功能重新连接受伤的视神经的策略一直是一个长期的挑战。通过对floxed小鼠基因的AAV串联辅助敲除条件敲除，我们最近做出了一个令人兴奋的发现，即在成年视网膜神经节细胞（RGC）中删除SOCS3（细胞因子信号的抑制3），使稳健的长距离轴突再生能够在潜在的信号范围内揭示了潜在的信号量，从而揭示了潜在的信号量，并揭示了MENDERING量的量。神经元。这项拟议的研究的目标是两倍：确定允许SOCS3缺失神经元中轴突再生的潜在机制，并评估再生轴突是否可以找到正常的投影途径和与其中心靶标的重新形态突触连接。