Sensory innervation-dependent transcriptional regulation in muscle

肌肉中感觉神经支配依赖性转录调节

• 批准号: 8036715
• 负责人: LARRY B FROMM
• 金额: $ 43.35万
• 依托单位: BALL 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: 2010-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8036715
• 关键词: Address; Afferent Neurons; Axon; Development; Elements; Fiber; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Length; Muscle; Muscle Cells; Muscle Fibers; Muscle Spindles; NRG1 gene; Nerve; Neuregulin 1; Neuregulins; Pathway interactions; Process; Proteins; Regulatory Element; Research; Response Elements; Sensory; Sensory Receptors; Signal Pathway; Signal Transduction; Signaling Protein; Structure; Transcription Regulatory Protein; Transcriptional Regulation; Uncertainty; cell type; genetic regulatory protein; insight; nerve supply; public health relevance; receptor; regenerative; response; sensory neuropathy; transcription factor

DESCRIPTION (provided by applicant): The proposed research addresses how sensory neuron innervation of muscle regulates gene expression during muscle spindle development. Muscle spindles are sensory receptors embedded within muscle that detect changes in muscle length. Each spindle is composed of specialized muscle fibers, known as intrafusal muscle fibers, and the endings of axons from sensory neurons that innervate these muscle fibers and that convey length information to the CNS. Formation of muscle spindles is regulated by inductive interactions between muscle fibers that ultimately will become intrafusal fibers and sensory axons that contact them. A critical part of this inductive process is neuregulin (NRG) 1, a secreted signaling protein, being released by sensory axons, and in turn activating its receptors, ErbB proteins, in muscle cells that are contacted. The proposed research focuses on the intracellular pathway activated by ErbBs, which is critical for muscle spindle formation but for the most part has not been determined. Despite the uncertainty about how the intracellular response occurs, one critical component that has been identified is the transcription factor Egr3, which is transcriptionally induced as part of NRG-ErbB signaling and in turn activates various target genes involved in formation of muscle spindles. The proposed research focuses on the signaling relay that acts upstream of Egr3 by identifying transcriptional regulatory proteins that are required for inducing transcription of Egr3 in response to NRG1 and determining how these transcriptional regulatory proteins are acted upon by the NRG1-ErbB pathway. In addition to providing insight into muscle spindle formation, results obtained from this research might also be applicable to how NRG1- ErbB signaling regulates gene expression in other cell types in which it functions, to how Egr3, which functions as part of a variety of signaling pathways, is regulated within these pathways, and to formation of other mechanosensory structures that are induced by the sensory axons that innervate them. Because certain sensory neuropathies involve destruction of nerves and their connections, understanding the signaling interactions that control formation of mechanosensory structures might suggest regenerative approaches for treating certain sensory neuropathies. PUBLIC HEALTH RELEVANCE: The proposed research addresses how sensory neuron innervation of muscle regulates gene expression during muscle spindle development and may also be applicable to formation of other mechanosensory structures that are induced by the sensory axons that innervate them. Certain sensory neuropathies involve destruction of nerves and their connections. Understanding the signaling interactions that control formation of muscle spindles and other mechanosensory structures might suggest regenerative approaches for treating certain sensory neuropathies.

描述（由申请人提供）：拟议的研究解决了肌肉的感觉神经元神经支配如何在肌梭发育过程中调节基因表达。肌梭是嵌入肌肉内的感觉受体，可检测肌肉长度的变化。每个纺锤体由特殊的肌纤维（称为梭内肌纤维）和感觉神经元的轴突末端组成，这些神经元支配这些肌纤维并将长度信息传递到中枢神经系统。肌梭的形成受到肌纤维之间的感应相互作用的调节，肌纤维最终将成为梭内纤维和接触它们的感觉轴突。这一诱导过程的关键部分是神经调节蛋白 (NRG) 1，它是一种分泌的信号蛋白，由感觉轴突释放，进而激活所接触的肌肉细胞中的受体 ErbB 蛋白。拟议的研究重点是 ErbB 激活的细胞内途径，该途径对于肌梭的形成至关重要，但大部分尚未确定。尽管细胞内反应如何发生尚不确定，但已确定的一个关键成分是转录因子 Egr3，它作为 NRG-ErbB 信号传导的一部分被转录诱导，进而激活参与肌梭形成的各种靶基因。拟议的研究重点关注作用于 Egr3 上游的信号转导，通过识别响应 NRG1 诱导 Egr3 转录所需的转录调节蛋白，并确定 NRG1-ErbB 通路如何作用这些转录调节蛋白。除了提供对肌纺锤形成的深入了解之外，从这项研究中获得的结果还可能适用于NRG1-ErbB信号如何调节其发挥作用的其他细胞类型中的基因表达，作为多种信号传导途径一部分的Egr3如何在这些途径中受到调节，以及由支配它们的感觉轴突诱导的其他机械感觉结构的形成。由于某些感觉神经病涉及神经及其连接的破坏，因此了解控制机械感觉结构形成的信号相互作用可能会建议治疗某些感觉神经病的再生方法。 公共健康相关性：拟议的研究探讨了肌肉的感觉神经元支配如何在肌梭发育过程中调节基因表达，并且也可能适用于由支配它们的感觉轴突诱导的其他机械感觉结构的形成。某些感觉神经病涉及神经及其连接的破坏。了解控制肌梭和其他机械感觉结构形成的信号相互作用可能会建议治疗某些感觉神经病的再生方法。