Gene Expression During Postnatal Development of the Central Auditory Pathway

描述（由申请人提供）：全面了解控制听觉系统产前和产后发育的遗传和环境因素对于构思和改进现有的治疗方法至关重要，这些方法可以解决临床人群中听觉功能受损的问题。由于它们的影响因个体和病因而异，这些因素结合起来以不同的方式塑造了听觉处理。基因表达的研究是揭示听觉系统底层结构及其如何随经验发展变化的重要工具。其中一些基因控制着所有中枢神经系统结构共同的一般代谢和调节功能。另一些则与特定的过程有关，如细胞通讯、运动、命运和分化。此外，它们的表达因年龄、大脑区域和感官体验而异。迄今为止，尚未对中枢听觉通路中的大多数结构生成全面的基因表达谱，也没有一个完整的基因表达谱适用于任何物种、任何年龄。本提案的科学目的是通过一项新的研究来解决这一需求，该研究旨在记录小鼠从出生后发育到成熟的关键阶段基因和蛋白质表达的变化。PI是一位成熟的听觉神经科学家，他的研究项目结合了神经解剖学和神经生理学方法，将大脑中听觉和多感觉回路的结构和功能联系起来。在职业发展方面，本提案的目的是通过为PI配备分子生物学的工具来扩大和丰富该研究计划的范围。在一位专家导师的监督下，PI将接受训练，以表征选定大脑区域的基因表达，然后在mRNA和蛋白质水平上定位这些大脑结构的转录本。以这种方式重组将使PI能够根据特定大脑区域的转录组谱来计划和开展研究。与现有的方法相比，全基因组表达谱方法在范围上更全面，更有效地连接结构和功能。该K18提案的科学和职业发展目标将在结合DNA微阵列分析，原位杂交和免疫组织化学的研究背景下实现：(1)鉴定出生后发育过程中听觉皮层，内侧膝状和下丘中差异表达的基因；(2)将选定基因的转录本定位到它们在细胞、分裂和每个结构的层板中的表达。这些努力将产生小鼠中枢听觉通路在出生后发育关键阶段的第一个基因表达目录，同时为PI研究大脑结构和功能增加一个重要的新维度。总的来说，这一提议推进了表征与沟通障碍（如听力损失、自闭症和中风）相关的关键神经生物学过程的努力。

DESCRIPTION (provided by applicant): A comprehensive understanding of the genetic and environmental factors that govern pre- and postnatal development of the auditory system is essential for conceiving of and improving existing therapeutic approaches that address impaired auditory function in clinical populations. Since their influence varies between individuals and by etiology, these factors combine to shape auditory processing in different ways. As a tool for revealing the underlying structure of the auditory system, and how it develops and changes with experience, studies of gene expression are indispensable. Some of these genes govern general metabolic and regulatory functions common to all central nervous system structures. Others are linked to specific processes, such as cell communication, motility, fate and differentiation. Moreover, their expression varies by age, between regions of the brain, and with sensory experience. To date, comprehensive gene expression profiles have not been generated for most structures in the central auditory pathway, and none are complete for any species at any age. The scientific aims of this proposal address this need in a novel study designed to document changes in gene and protein expression in the mouse at key stages of postnatal development to maturity. The PI is an established auditory neuroscientist whose research program combines neuroanatomical and neurophysiological methods to link structure and function in auditory and multisensory circuits in the brain. In terms of career development, the purpose of this proposal is to expand and enrich the scope of this research program by equipping the PI with the tools of molecular biology. Under the supervision of an expert mentor, the PI will be trained to characterize gene expression in selected brain areas, and then follow up by localizing transcripts to those brain structures at the mRNA and protein levels. Retooling in this manner will enable the PI to plan and conduct studies that are informed by the transcriptome profile of specific brain regions. Compared to existing strategies, the whole genome expression profiling approach is more comprehensive in scope and more effectively bridges structure and function. The scientific and career development goals of this K18 proposal will be achieved in the context of a study that combines DNA microarray analysis, in situ hybridization, and immunohistochemistry to: (1) identify genes that are differentially expressed in auditory cortex, medial geniculate, and inferior colliculus during postnatal development; and (2) localize the transcripts of selected genes to their expression within the cells, divisions, and laminae of each structure. These efforts will generate the first catalog of gene expression in the mouse central auditory pathway at key stages of postnatal development, while adding an important new dimension to studies of brain structure and function by the PI. Overall, this proposal advances efforts to characterize key neurobiological processes associated with communication disorders, such as hearing loss, autism, and stroke.