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: 8226226
• 负责人: Jason Marshall Newbern
• 金额: $ 8.7万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8226226
• 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; 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. PUBLIC HEALTH RELEVANCE: Mutations in the ERK/MAPK intracellular signaling cascade are an important cause of a subset of human syndromes that exhibit neurodevelopmental delay and learning impairment. The execution of this proposal will be of interest to clinical disciplines that are exploring ERK1/2 as a therapeutic target or seeking to understand and reverse the pathology of developmental syndromes resulting from mutations in ERK/MAPK signaling components.

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起重要作用。ERK/MAPK信号的遗传破坏与神经发育综合征有关，但我们对这一途径在发育中的大脑中的功能的理解是初步的。本职业发展建议旨在确定ERK/MAPK在抑制性神经回路中的确切作用，该神经回路被认为在神经发育综合征中被破坏。在被指导阶段，ERK/MAPK信号在皮层抑制性中间神经元发育中的精确功能将被确立（Aim 1）。ERK/MAPK信号条件增益和损失的最终小鼠模型将生成并使用先进的成像和电生理技术进行研究。重要的是，受损的抑制性中间神经元是否可以在成年小鼠异常ERK/MAPK活性正常化后修复，将在指导和独立阶段进行测试（Aim 2）。最后，在独立期的体内抑制性中间神经元中，将对促进ERK/MAPK效应的基因表达的全局变化进行特异性评估（目的3）。这些数据对于理解由ERK/MAPK信号组分突变引起的人类综合征中神经回路缺陷的发展和逆转至关重要。我的长期目标是获得学术职位，研究神经发育障碍，特别是与ERK/MAPK功能障碍相关的神经回路功能障碍和恢复机制。这方面的研究需要电生理学和皮层发育方面的训练。北卡罗来纳大学是完成这一应用的指导阶段的杰出机构，主要是由于丰富的基础科学和临床研究人员对许多神经发育障碍进行跨学科研究。除了Snider博士丰富的经验和杰出的领导能力外，北卡罗来纳大学的一些杰出科学家将提供电生理培训，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，这将有助于本提案的两个阶段。总的来说，这份提案所支持的培训经历将对我获得教员职位和建立独立实验室至关重要。