Soluble Neuregulins in Neuromuscular and Peripheral Nerve Development

可溶性神经调节蛋白在神经肌肉和周围神经发育中的作用

基本信息

批准号：
8020025
负责人：
JEFFREY A LOEB
金额：
$ 32.59万
依托单位：
WAYNE STATE UNIVERSITY
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：
2010-02-15 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8020025
关键词：
Affect Afferent Neurons Axon Basal lamina Binding Biological Brain-Derived Neurotrophic Factor Cell Communication Cell Proliferation Cell Survival Cells Central Nervous System Diseases Chick Embryo Cholinergic Receptors Communication Development Developmental Process Differentiation and Growth Disease Electroporation Embryo Extracellular Matrix Family Feedback GDNF gene Growth Factor Heparan Sulfate Proteoglycan Heparin Binding Heparitin Sulfate In Vitro Laboratories Measures Mediating Membrane Methods Modeling Motor Motor Neurons Multiple Sclerosis Mus Muscle Muscle Cells NRG1 gene Nerve Nervous system structure Neuraxis Neuregulins Neuroglia Neuromuscular Diseases Neuromuscular Junction Neurons Neuropathy Pathway interactions Peripheral Peripheral Nerves Peripheral Nervous System Diseases Phosphorylation Postsynaptic Membrane Principal Investigator Protein Isoforms Protein Kinase C RNA Splicing Role Schizophrenia Schwann Cells Serine Signal Transduction Site Small Interfering RNA Spatial Distribution Staging Synapses System Testing Therapeutic Therapeutic Uses Work cell type design effective therapy improved in vivo knock-down loss of function migration myelination neuromuscular neurotrophic factor new therapeutic target novel novel therapeutics programs public health relevance response

项目摘要

DESCRIPTION (provided by applicant): The neuregulins (NRGs) are a family of neuronally-derived growth and differentiation factors that 'target" the axoglial interface and neuromuscular junctions (NMJs) through both soluble, heparin-binding and membrane anchored alternatively spliced forms. They promote proliferation, migration, survival, and myelination of both peripheral and central glia. At the NMJ, their role is less clear, but heparin-binding forms accumulate within the basal lamina of NMJs at distinct developmental stages and induce acetylcholine receptors, suggesting that they promote synaptic strength. Given the close proximity of the axon to both muscle and Schwann cell targets, the direct and indirect effects of NRG1 on muscle and nerve have been difficult to establish. Our laboratory focuses on the soluble, heparin-binding forms of NRG1. We found that soluble forms of NRG1 are rapidly released from both sensory and motor neuron axons in response to Schwann cell and muscle-derived neurotrophic factors such as BDNF and GDNF, and that this pathway is regulated by protein kinase C. Once released, NRG1 becomes concentrated within the nerve and at NMJs through highly specific interactions with heparan sulfate proteoglycans (HSPGs). Here, we will explore how NRG1 promotes peripheral nerve and NMJ development in both chick and mouse embryos through two sequential mechanisms. (1) Regulated release from axons by Schwann cell and muscle-derived neurotrophic factors, (2) Neurotrophic factor-induced PKC signaling. Once released from axons, NRG1 will be localized to sites where it accumulates in the extracellular matrix through developmentally-expressed heparan-sulfate proteoglycans (HSPGs). In an important part of these studies, we will also test a novel therapeutic method to target biological therapeutics to axoglial and neuromuscular junctions using NRG1's heparin-binding domain as a specific targeting motif. Relevance: To date there are few effective treatments for diseases of the peripheral and central nervous systems. A promising means to overcome this is to develop biologically-driven therapeutics that use growth factors required for nervous system formation. This proposal will attempt to overcome some off the major limitations in developing such therapeutics through an improved understanding of normal development and improved ways to target novel therapeutics within the nervous system. PUBLIC HEALTH RELEVANCE: Understanding the mechanisms that regulate the release and localization of neuregulin at the peripheral nerve and neuromuscular junction will be critical to design effective therapeutics for diseases of peripheral nerve and neuromuscular disorders, such as neuropathy andALS,aswellasCNSdisorders,suchasmultiplesclerosisandschizophrenia.Treatmentscould consist of promoting neuregulin or neurotrophin signaling, and/or promoting neuregulin release through activation of PKC-4 signaling. Our studies also test a more general 'targeting' system we invented that effectively delivers therapeutics to specific cell types through their unique heparan sulfate composition.

描述（由申请人提供）：神经调节蛋白（NRG）是一类神经源性生长和分化因子，通过可溶性、肝素结合和膜锚定的选择性剪接形式“靶向”轴神经胶质界面和神经肌肉接头（NMJ）。它们促进 NMJ 外周和中央神经胶质细胞的增殖、迁移、存活和髓鞘形成，其作用尚不清楚，但与肝素结合。 NRG1 的形式在不同的发育阶段在 NMJ 的基底层内积累并诱导乙酰胆碱受体，这表明它们可以促进突触强度，因为轴突与肌肉和雪旺细胞靶标非常接近，NRG1 对肌肉和神经有直接和间接的影响。我们的实验室专注于可溶性肝素结合形式的 NRG1，我们发现可溶性形式的 NRG1 可以从感觉神经元和运动神经元中快速释放。轴突对雪旺细胞和肌肉源性神经营养因子（如 BDNF 和 GDNF）做出反应，并且该通路受蛋白激酶 C 调节。一旦释放，NRG1 通过与硫酸乙酰肝素蛋白聚糖的高度特异性相互作用，集中在神经内和 NMJ 处。 HSPG）。在这里，我们将探讨 NRG1 如何通过两种连续机制促进鸡和小鼠胚胎中的周围神经和 NMJ 发育。 (1) 施万细胞和肌肉源性神经营养因子调节轴突释放，(2) 神经营养因子诱导的 PKC 信号传导。一旦从轴突释放，NRG1 将定位到通过发育表达的硫酸乙酰肝素蛋白聚糖 (HSPG) 在细胞外基质中积累的位点。在这些研究的一个重要部分中，我们还将测试一种新的治疗方法，使用 NRG1 的肝素结合结构域作为特定的靶向基序，将生物疗法靶向轴胶质细胞和神经肌肉接头。相关性：迄今为止，针对周围和中枢神经系统疾病的有效治疗方法很少。克服这一问题的一个有希望的方法是开发生物驱动的疗法，利用神经系统形成所需的生长因子。该提案将试图通过提高对正常发育的理解和改进针对神经系统内新疗法的方法来克服开发此类疗法的一些主要限制。公共健康相关性：了解调节神经调节蛋白在周围神经和神经肌肉接头处的释放和定位的机制对于设计治疗周围神经和神经肌肉疾病（例如神经病和 ALS）以及中枢神经系统疾病（例如多发性硬化症和精神分裂症）的有效疗法至关重要。促进神经调节蛋白或神经营养蛋白信号传导，和/或通过激活促进神经调节蛋白释放PKC-4 信号传导。我们的研究还测试了我们发明的更通用的“靶向”系统，该系统通过其独特的硫酸乙酰肝素成分有效地向特定细胞类型提供治疗。