The In Vivo Role of ERK1/2 Signaling in Peripheral Nervous System Development

ERK1/2 信号传导在周围神经系统发育中的体内作用

• 批准号: 7676488
• 负责人: Jason Marshall Newbern
• 金额: $ 5.01万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676488
• 关键词: Address; Afferent Neurons; Alleles; Axon; Biological Models; Cell Differentiation process; Cell Proliferation; Clinical; Complex; Conflict (Psychology); Data; Development; Discipline; Embryo; Exhibits; Extracellular Matrix; Fellowship; Financial compensation; Genetic; Growth Factor; In Vitro; MAPK1 gene; MAPK3 gene; MAPK7 gene; MAPK7 gene; Malignant Neoplasms; Mediator of activation protein; Mus; Mutation; Natural regeneration; Nerve Regeneration; Neurons; Pathogenesis; Pathway interactions; Peripheral; Peripheral Nervous System; Play; Preparation; Process; Proteins; Role; Schwann Cells; Signal Transduction; Spinal Ganglia; Staging; Stimulus; Study models; Syndrome; Technology; Training; autism spectrum disorder; axon growth; cell type; craniofacial; extracellular; genetic analysis; glial cell development; in vivo; interest; myelination; nervous system development; painful neuropathy; programs; promoter; recombinase; research study; response; therapeutic target

DESCRIPTION (provided by applicant): The Extracellular signal-Regulated protein Kinase1/2 (ERK1/2, classical MARK) intracellular signal transduction cascade is activated by numerous extracellular stimuli that play important roles in various aspects of nervous system development, plasticity, and regeneration. Although ERK1/2 is thought to be vital for a number of processes its precise functional role has not been adequately analyzed. To better clarify the role of ERK1/2 signaling in peripheral nervous system development, we have utilized Cre/loxp technology to conditionally inactivate ERK1/2 specifically in sensory neurons and Schwann cells at early stages of development. The precise in vivo function of ERK1/2 signaling in Schwann cell differentiation and myelination and sensory neuron axon growth will be defined. The ability of the related kinase, ERK5, to compensate for loss of ERK1/2 will also be analyzed. These data will further our understanding of the complex functions regulated by ERK1/2 in separate cell types and clarify the intracellular pathways utilized by a trophic factors important for nervous system development. Summary Statement: Genetic or sporadic disruption of ERK1/2 signaling has been implicated in craniofacial syndromes, autism spectrum disorders, neuropathic pain, neurofibramatosis, and various cancers, yet our understanding of the functions of this pathway remain incomplete. The data arising from the execution of this proposal will be of interest to clinical disciplines; exploring ERK1/2 or ERK5 signaling as a therapeutic target, seeking to understand the pathogenesis of developmental syndromes resulting from mutations in regulators of ERK1/2 signaling, or attempting to reactivate neuronal or glial programs to induce or modify nervous system regeneration.

描述（由申请人提供）：细胞外信号调节蛋白激酶1/2（ERK1/2，经典MARK）细胞内信号转导级联被众多细胞外刺激激活，在神经系统发育、可塑性和再生的各个方面发挥重要作用。尽管 ERK1/2 被认为对许多过程至关重要，但其精确的功能作用尚未得到充分分析。为了更好地阐明 ERK1/2 信号在周围神经系统发育中的作用，我们利用 Cre/loxp 技术有条件地灭活 ERK1/2，特别是在发育早期阶段的感觉神经元和雪旺细胞中。 ERK1/2 信号在雪旺细胞分化和髓鞘形成以及感觉神经元轴突生长中的精确体内功能将得到定义。还将分析相关激酶 ERK5 补偿 ERK1/2 损失的能力。这些数据将进一步加深我们对不同细胞类型中 ERK1/2 调节的复杂功能的理解，并阐明对神经系统发育重要的营养因子所利用的细胞内途径。摘要：ERK1/2 信号传导的遗传性或偶发性破坏与颅面综合征、自闭症谱系障碍、神经性疼痛、神经纤维瘤病和各种癌症有关，但我们对该通路功能的理解仍然不完整。执行该提案所产生的数据将引起临床学科的兴趣；探索 ERK1/2 或 ERK5 信号传导作为治疗靶点，寻求了解 ERK1/2 信号传导调节因子突变引起的发育综合征的发病机制，或尝试重新激活神经元或神经胶质程序以诱导或改变神经系统再生。