Expanding the utility of Drosophila as a model for hearing research

扩大果蝇作为听力研究模型的用途

• 批准号: 7198420
• 负责人: GRACE E BOEKHOFF-FALK
• 金额: $ 25.35万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7198420
• 关键词: Achievement; Animal Model; Auditory; Auditory system; Biological; Biology; CCAAT displacement protein; Cell Cycle Regulation; Cellular biology; Defect; Development; Drosophila genus; Drosophila melanogaster; Gene Targeting; Genes; Genetic; Genetic Screening; Goals; Hearing; Hearing Impaired Persons; Homologous Gene; Human; Insecta; Investigation; Laboratories; Light; Maintenance; Mammals; Modeling; Nerve Degeneration; Organ; Pathway interactions; Proteins; Research; Structure; System; Techniques; Tumor Suppressor Proteins; Work; base; chromatin immunoprecipitation; deafness; developmental genetics; homeodomain; in vivo; innovation; insight; mutant; novel; research study; technique development; transcription factor

DESCRIPTION (provided by applicant): The goal of the research described in this proposal is to advance our understanding of fundamental biological mechanisms used to construct auditory and other mechanosensory systems. The experiments proposed here have two objectives. First, we plan to develop techniques that will be generally applicable to the investigation of auditory systems from insects to mammals. Second, we will use these techniques to study development and differentiation of the Drosophila (fruitfly) auditory organ. Together these experiments will expand the utility of Drosophila as a model for hearing research while providing insight into the differentiation and function of the Drosophila auditory organ. The experiments are focused the cut gene. We have shown that cut mutants are deaf and that their deafness is correlated both with defects in the mechanotransducing structures of the auditory organ and with neurodegeneration. The approaches used to date have provided only a partial picture of cut function with little insight into specific mechanisms of cut action. Here, I propose to develop and utilize an innovative and powerful combination of chromatin immunoprecipitation (ChIP) and microarray expression analysis to identify genes regulated by Cut. cut encodes an unusual homeodomain transcription factor whose human homolog, CCAAT-displacement protein (CDP)/CUTL1, has been implicated in cell cycle regulation and functions as a tumor suppressor. The proposed experiments will significantly expand our understanding of what Cut/CDP proteins do and how they do it. Fields that will be substantially impacted by these studies include: hearing, mechanosensation in general, Cut/CDP biology, and transcription factor biology. In light of the emerging developmental genetic parallels between Drosophila and vertebrate auditory organ development, I anticipate that information generated by the proposed experiments also will be relevant to human hearing.

描述（由申请人提供）：本提案中描述的研究目标是促进我们对用于构建听觉和其他机械感觉系统的基本生物学机制的理解。这里提出的实验有两个目标。首先，我们计划开发的技术，将普遍适用于从昆虫到哺乳动物的听觉系统的调查。其次，我们将利用这些技术来研究果蝇（果蝇）听觉器官的发育和分化。总之，这些实验将扩大果蝇作为听力研究模型的实用性，同时提供深入了解果蝇听觉器官的分化和功能。实验主要集中在cut基因上。我们已经证明，切割突变体是耳聋的，他们的耳聋与听觉器官的机械转导结构缺陷和神经退行性变相关。到目前为止，所使用的方法只提供了一个局部的图片削减功能与削减行动的具体机制很少深入了解。在这里，我建议开发和利用一个创新的和强大的染色质免疫沉淀（ChIP）和微阵列表达分析相结合，以确定基因调控的削减。cut编码一种不寻常的同源域转录因子，其人类同源物CCAAT-置换蛋白（CDP）/CUTL 1与细胞周期调控有关，并作为肿瘤抑制因子发挥作用。拟议的实验将大大扩展我们的理解切/CDP蛋白做什么，他们是如何做到这一点。这些研究将产生重大影响的领域包括：听力，机械感觉一般，切/CDP生物学和转录因子生物学。鉴于果蝇和脊椎动物听觉器官发育之间正在出现的发育遗传相似性，我预计拟议的实验产生的信息也将与人类听觉相关。