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The Transcriptomic and Biophysical Basis of Mechanosensory Submodality: A Drosophila Model Organ Study

机械感觉亚模态的转录组学和生物物理基础：果蝇模型器官研究

基本信息

批准号：
BB/L02084X/1
负责人：
Joerg Albert
金额：
$ 52.22万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FL02084X%2F1
关键词：
Transcriptomic Biophysical Basis Mechanosensory Submodality

项目摘要

Mechanosensory organs directly couple the mechanical energy of a stimulus to the open-state of an ion channel in the membrane of a mechanosensory cell. This process, known as mechanotransduction, lies at the heart of all mechanosensation. Conceptually, it is clear that the specific nature of this coupling will distinguish, and define, the various mechanosensory submodalities (such as sound, touch, balance, wind, pain, gravity or proprioception). But the concept is misleading in its clarity. It hides the fact that it is unclear how that coupling should differ between, say, a proprioceptive and tactile hair on a spider leg, a vestibular hair cell, or an auditory hair cell in the vertebrate cochlea. Adding darkness to short sight, the molecular identities of the actual transducer channels are still unknown for all of the above given examples. But even if we did know all the respective requirements, we would still not know how these are implemented molecularly for submodality-specific mechanotransduction, to occur. One of the most amenable mechanosensory model organs, the Drosophila Johnston Organ (JO), sits in the 2nd antennal segment and harbours discrete populations of mechanosensory neurons which have been linked to the submodalities of wind/gravity and sound. However, all neurons attach to the same receiver structure, the third antennal segment. Large parts of the submodality-specific adaptations thus have to be implemented downstream of the receiver on the level of the respective cellular and molecular components. We intend to carry out a comprehensive molecular, and functional, dissection of modality-specific mechanotransduction in JO.We will first profile the specific mRNA transcriptomes, (i.e. the complete sets of produced mRNAs) for different types of neuronal and non-neuronal cells. Such cell-type-specific transcriptomic analyses will unveil the molecular (and cellular) divisions of labour in JO and help identify the distinct roles of individual genes for subset-specific mechanotransduction and mechanosensory behaviours. Our behavioural analyses will use novel tools that we have specifically devised for this project. Combining molecular and biophysical analyses (laser vibrometry, extracellular and intracellular recordings) with predictive computational tools, this project will put particular emphasis on the identification of modality-specific differences in higher order regulatory genes, such as specific transcription factors. The identification of modality-specific transcription factors is expected to enable the identification of distinct modules of sensory transduction, which act as functional units within mechanosensory cells of different modalities.There is robust evidence that the sensory organs of different species, e.g. the ears of flies and the ears of humans, share multiple functional and molecular similarities. Likewise, different sensory organs within the same species, e.g. the ears and the eyes of flies display striking molecular and mechanistic overlap. Understanding how the underlying transcriptional pathways, which can be expected to be conserved across the animal kingdom, are being recombined during the process of evolution to create sensory systems of various modalities and submodalities will be of great value for better understanding of the myriad of human disease syndromes such as Usher syndrome Type IIA + IIIA or Bardet-Biedl syndrome, which simultaneously affect multiple sensory systems. Eventually, this research into the molecular and mechanistic fundaments of sensory modality will lead the way towards new therapeutic avenues.

机械感觉器官将刺激的机械能直接耦合到机械感觉细胞膜中离子通道的开放状态。这个过程被称为机械传导，是所有机械感觉的核心。从概念上讲，很明显，这种耦合的具体性质将区分和定义各种机械感觉子模态（例如声音、触摸、平衡、风、疼痛、重力或本体感觉）。但这个概念的清晰度具有误导性。它掩盖了这样一个事实：目前尚不清楚蜘蛛腿上的本体感觉毛发和触觉毛发、前庭毛细胞或脊椎动物耳蜗中的听觉毛细胞之间的耦合有何不同。给短视带来了黑暗，对于所有上述示例来说，实际传感器通道的分子特性仍然未知。但即使我们确实知道所有相应的要求，我们仍然不知道如何在分子上实现这些要求以实现子模态特异性的机械转导。果蝇约翰斯顿器官 (JO) 是最适合的机械感觉模型器官之一，位于第二触角节段，拥有离散的机械感觉神经元群体，这些神经元与风/重力和声音的亚模态相关。然而，所有神经元都附着在相同的接收器结构上，即第三触角节。因此，大部分子模态特定的适应必须在接收器下游的相应细胞和分子成分的水平上实现。我们打算对 JO 中的模态特异性机械转导进行全面的分子和功能剖析。我们将首先分析不同类型神经元和非神经元细胞的特定 mRNA 转录组（即产生的完整 mRNA 集）。这种细胞类型特异性转录组分析将揭示 JO 中的分子（和细胞）分工，并有助于识别单个基因对于子集特异性机械转导和机械感觉行为的独特作用。我们的行为分析将使用我们专门为该项目设计的新颖工具。该项目将分子和生物物理分析（激光振动测量、细胞外和细胞内记录）与预测计算工具相结合，将特别强调识别高阶调控基因（例如特定转录因子）中的模式特异性差异。模态特异性转录因子的识别有望能够识别不同的感觉转导模块，这些模块在不同模态的机械感觉细胞内充当功能单元。有强有力的证据表明，不同物种的感觉器官，例如，感觉器官。苍蝇的耳朵和人类的耳朵具有多种功能和分子相似之处。同样，同一物种内的不同感觉器官，例如果蝇的耳朵和眼睛显示出惊人的分子和机械重叠。了解在整个动物界中保守的潜在转录途径如何在进化过程中重新组合以创建各种模式和子模式的感觉系统，对于更好地理解无数人类疾病综合征（例如亚瑟综合征 IIA + IIIA 或 Bardet-Biedl 综合征）具有重要价值，这些综合征同时影响多个感觉系统。最终，这项对感觉方式的分子和机制基础的研究将引领新的治疗途径。