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）：神经素（NRGS）是神经源性生长和分化因子的家族，它们“针对”轴突界面和神经肌肉连接（NMJS），都可以通过可溶性，肝素结合和膜固定的形式固定。它们促进外围和中央胶质的增殖，迁移，生存和髓鞘形成，它们的作用不太清楚，但是在NMJ的基底层中积累了肝素结合形式，在不同的发育阶段并诱导乙酰胆碱受体，这表明它们促进了突触强度，鉴于轴突与肌肉和Schwann细胞靶标的紧密相邻，NRG1对肌肉和神经的直接和间接影响很难确定我们的实验室。。通过与硫酸乙酰肝素蛋白聚糖（HSPGS）高度特异性相互作用，将其集中在神经内和NMJ中。在这里，我们将探讨NRG1如何通过两种顺序机制促进雏鸡和小鼠胚胎中的周围神经和NMJ发育。（1）通过雪旺细胞和肌肉衍生的神经营养因子从轴突中释放，（2）神经营养因子诱导的PKC信号传导。一旦从轴突释放出来，NRG1将定位到通过发育表达的肝素硫酸盐蛋白聚糖（HSPGS）中积累在细胞外基质中的位点。在这些研究的重要部分中，我们还将使用NRG1的肝素结合结构域作为特定的靶向基序来测试一种新型的治疗方法，以靶向生物学治疗剂对轴突和神经肌肉连接。相关性：迄今为止，几乎没有有效的外围和中枢神经系统疾病的治疗方法。克服这一点的一种有希望的方法是开发以生物学驱动的治疗剂，使用神经系统形成所需的生长因子。该提案将试图通过对正常发育的改进以及改善神经系统中新型治疗剂的方法来克服开发这种治疗剂的主要局限性。公共卫生相关性：了解调节神经调节蛋白在周围神经和神经肌肉连接处的释放和定位的机制对于设计有效的外周神经和神经肌肉疾病疾病的疾病至关重要通过激活PKC-4信号传导来促进神经调节蛋白或神经营养蛋白信号传导和/或促进神经结合蛋白释放。我们的研究还测试了一个更通用的“靶向”系统，我们发明了通过其独特的硫酸乙酰肝素组成为特定细胞类型提供治疗剂。