ERK/MAPK regulation of cortical inhibitory interneurons

描述(申请人提供)：ERK/MAPK细胞内信号转导通路由细胞外刺激激活，细胞外刺激在神经系统发育和可塑性中发挥重要作用。ERK/MAPK信号通路的遗传干扰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的功能的了解还很初级。这份职业发展提案试图定义ERK/MAPK在被认为在神经发育综合征中被破坏的抑制性神经回路中的确切作用。在指导阶段，将建立ERK/MAPK信号在皮质抑制中间神经元发育中的确切功能(目标1)。我们将建立明确的ERK/MAPK信号获得和丢失的小鼠模型，并利用先进的成像和电生理学技术进行研究。重要的是，在成年小鼠ERK/MAPK异常活性正常化后，受损的抑制性中间神经元是否能够修复，将在指导阶段和独立阶段进行测试(目标2)。最后，有助于ERK/MAPK效应的基因表达的全球变化将在独立阶段的体内抑制性中间神经元中进行专门评估(目标3)。这些数据对于理解由ERK/MAPK信号成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地位，研究神经发育障碍的神经回路功能障碍和修复机制，特别是与ERK/MAPK功能障碍相关的功能障碍。这项研究需要接受电生理学和大脑皮层发育方面的培训。北卡罗来纳大学是完成这项申请的指导阶段的杰出机构，主要是因为有大量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。除了斯奈德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的科学家还将提供电生理培训、正式的课堂作业和科学指导。已经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。总体而言，这项提议所支持的培训经验将对我获得教职任命和建立独立实验室至关重要。

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.