ERK/MAPK regulation of cortical inhibitory interneurons

皮质抑制性中间神经元的 ERK/MAPK 调节

• 批准号: 8703421
• 负责人: Jason Marshall Newbern
• 金额: $ 24.7万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703421
• 关键词: Address; Adult; Alleles; Appointment; Basic Science; Binding; Brain; Cells; Clinical; Cognitive; Cues; Data; Defect; Development; Developmental Delay Disorders; Discipline; Electrophysiology (science); Exhibits; Faculty; Family; Functional disorder; Gene Expression; Genetic; Global Change; Goals; Human; Image; Impairment; Inhibitory Synapse; Institution; Interdisciplinary Study; Internal Ribosome Entry Site; Interneurons; Intraventricular Injections; Knock-in Mouse; Laboratories; Leadership; Learning; Ligands; Link; MAP Kinase Gene; MAPK1 gene; MAPK3 gene; Mentors; Microarray Analysis; Morphology; Mus; Mutant Strains Mice; Mutation; Myoepithelial cell; NF1 gene; Neocortex; Neurodevelopmental Disorder; Neurologic; Pathogenesis; Pathology; Pathway interactions; Patients; Phase; Play; Positioning Attribute; RNA Binding; Regulation; Research; Research Personnel; Role; Scientist; Seizures; Signal Transduction; Stimulus; Synapses; Syndrome; Techniques; Testing; Therapeutic; Training; Transgenes; Work; adeno-associated viral vector; analog; career development; excitatory neuron; experience; extracellular; gain of function; in vivo; inhibitor/antagonist; interest; loss of function; mouse model; mutant; neocortical; nervous system development; neural circuit; neuronal cell body; neurotransmission; novel therapeutics; postnatal; progenitor; ranpirnase; repaired; response; restoration; therapeutic target

DESCRIPTION (provided by applicant): The ERK/MAPK intracellular signal transduction cascade is activated by extracellular stimuli that play important roles in nervous system development and plasticity. Genetic disruption of ERK/MAPK signaling has been implicated in neurodevelopmental syndromes, yet our understanding of the functions of this pathway in the developing brain is rudimentary. This career development proposal seeks to define the precise role of ERK/MAPK in inhibitory neural circuits that are thought to be disrupted in neurodevelopmental syndromes. During the mentored phase, the precise functions of ERK/MAPK signaling in cortical inhibitory interneuron development will be established (Aim 1). Definitive mouse models for conditional gain and loss of ERK/MAPK signaling will be generated and studied with advanced imaging and electrophysiological techniques. Importantly, whether damaged inhibitory interneurons can be repaired following the normalization of aberrant ERK/MAPK activity in adult mice will be tested during both the mentored and independent phase (Aim 2). Finally, the global changes in gene expression that contribute to ERK/MAPK effects will be assessed specifically in inhibitory interneurons in vivo during the independent phase (Aim 3). These data will be essential for understanding the development and reversal of neural circuit defects in human syndromes resulting from mutations in ERK/MAPK signaling components. My long term goal is to obtain an academic position and study mechanisms of neural circuit dysfunction and restoration in neurodevelopmental disorders, particularly those linked to ERK/MAPK dysfunction. This line of research will require training in electrophysiology and cortical development. UNC is an outstanding institution to complete the mentored phase of this application, primarily due to the wealth of basic science and clinical researchers performing interdisciplinary research on numerous neurodevelopmental disorders. In addition to Dr. Snider's extensive experience and outstanding leadership, a number of exceptional scientists at UNC will provide electrophysiological training, formal class work, and scientific guidance. Relationships with outstanding researchers at other institutions have been established that will contribute to both phases of this proposal. Overall, the training experiences to be supported by this proposal will be critical for me to obtain a faculty appointment and establish an independent laboratory.

描述（由申请人提供）： ERK/MAPK细胞内信号转导级联被细胞外刺激激活，在神经系统发育和可塑性中发挥重要作用。ERK/MAPK信号转导的遗传破坏与神经发育综合征有关，但我们对这一通路在发育中的大脑中的功能的理解是基本的。这个职业发展建议旨在定义ERK/MAPK在抑制性神经回路中的确切作用，这些神经回路被认为在神经发育综合征中被破坏。 在指导阶段，ERK/MAPK信号传导在皮层抑制性中间神经元发育中的精确功能将被建立（目标1）。将产生ERK/MAPK信号传导的条件性获得和丧失的连续小鼠模型，并使用先进的成像和电生理技术进行研究。重要的是，在成年小鼠中异常ERK/MAPK活性正常化后，受损的抑制性中间神经元是否可以修复，将在指导和独立阶段进行测试（目标2）。最后，将在独立阶段期间在体内抑制性中间神经元中特异性地评估有助于ERK/MAPK效应的基因表达的总体变化（目的3）。这些数据将是必不可少的理解的发展和逆转的神经回路缺陷，在人类综合征导致的突变ERK/MAPK信号转导成分。 我的长期目标是获得一个学术职位，并研究神经回路功能障碍和神经发育障碍的恢复机制，特别是那些与ERK/MAPK功能障碍有关的机制。这项研究需要在电生理学和皮层发育方面进行培训。ESTA是一个优秀的机构来完成这个应用程序的指导阶段，主要是由于基础科学和临床研究人员的财富进行跨学科研究的许多神经发育障碍。Snider博士的丰富经验和杰出的领导能力，一些杰出的科学家在ESTA将提供电生理学培训，正式的课堂作业，和科学指导。与其他机构的杰出研究人员建立了关系，这将有助于这一建议的两个阶段。总的来说，本建议书所支持的培训经验对我获得教师任命和建立独立实验室至关重要。