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

• 批准号: 8220869
• 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
• 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/8220869
• 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

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）是一个神经源性生长和分化因子家族，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）。它们促进周围和中央胶质细胞的增殖、迁移、存活和髓鞘形成。在NMJ，它们的作用不太清楚，但肝素结合形式在不同的发育阶段积累在NMJ的基底层内，并诱导乙酰胆碱受体，这表明它们促进突触强度。由于轴突与肌肉和许旺细胞靶点非常接近，NRG 1对肌肉和神经的直接和间接影响难以确定。我们的实验室专注于NRG 1的可溶性肝素结合形式。我们发现，可溶形式的NRG 1从感觉和运动神经元轴突中快速释放，以响应雪旺细胞和肌源性神经营养因子如BDNF和GDNF，并且该途径受蛋白激酶C调节。一旦释放，NRG 1通过与硫酸乙酰肝素蛋白聚糖（HSPG）的高度特异性相互作用而集中在神经内和NMJ处。在这里，我们将探讨如何NRG 1促进周围神经和NMJ发育鸡和小鼠胚胎通过两个顺序的机制。(1)雪旺细胞和肌源性神经营养因子对轴突释放的调节作用。（2）神经营养因子诱导的PKC信号通路。一旦从轴突释放，NRG 1将定位于其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NRG 1的肝素结合结构域作为特异性靶向基序，将生物疗法靶向轴神经胶质和神经肌肉接头。 相关性：迄今为止，对外周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治疗方法，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更好理解和在神经系统内靶向新疗法的改进方法来克服开发此类疗法的一些主要限制。 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接头处释放和定位的机制对于设计有效治疗周围神经和神经肌肉疾病（如神经病和ALS）以及中枢神经系统疾病（如多发性硬化症和精神分裂症）至关重要。治疗可包括促进神经调节蛋白或神经营养因子信号传导和/或通过激活PKC-4信号传导促进神经调节蛋白释放。我们的研究还测试了我们发明的一种更通用的“靶向”系统，该系统通过其独特的硫酸乙酰肝素成分有效地将治疗药物递送到特定的细胞类型。