Structural organisations underlying auditory sensitivity

听觉敏感性的结构组织

• 批准号: BB/I02123X/1
• 负责人: Andrew Forge
• 金额: $ 52.31万
• 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: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI02123X%2F1
• 关键词: Structural; organisations; underlying; auditory; sensitivity

Most cellular functions depend upon assemblies of interacting molecules, and upon the ways in which those complexes are organised within a cell. Moreover, cells themselves are organised to compartmentalise different activities into different regions while at the same time enabling the integration of those activities that is necessary for the cell to function as it should. There is, thus, a very close relationship between cellular architecture and cell function. Consequently, crucial to understanding how different molecules are integrated into a cell to support its function, and how cells go wrong when molecular function is disrupted during disease, is knowledge of the three-dimensional cellular architecture at levels of resolution that enable visualisation of macromolecular assemblies and the cellular context in which they normally function. Electron microscopy reveals such structural details across a range from the approximate dimension of macromolecules up to the level of the whole cell. Three-dimensional information can be obtained from tissue sections examined by electron microscopy by the application of now established methods for 'electron tomography'. In this technique, a collection of images of the same structure is taken from many different angles. When these images are assembled together, a three-dimensional view of the structure is obtained. From this it is possible to identify how structures are associated with one another, for example how one molecular complex interacts with another, or at a lower level of resolution, how organelles within a cell are distributed and whether there is continuity between them. If tissue is prepared for microscopy by means that preserve the natural state, which can be achieved by freezing them very rapidly before processing, it becomes possible to obtain details of sub-cellular structures in a close-to-life condition in their true context inside the cell. This project will apply these modern methods to assess features of the cellular architecture of the sensory tissues of the inner ear. These tissues are responsible for the sense of hearing and maintenance of balance and they are remarkably three-dimensional in their architecture. Individual sensory 'hair' cells are cylindrical and bear at their top ends an organised bundle of projections, deflections of which in response to sound vibrations (hearing) or motion (balance) lead to signalling to the nerves at the bottom of the cell. Each hair cell is surrounded by cells that provide structural support. The project will explore the organisation of structures crucial to the cell's ability to faithfully generate appropriate neural output in response to mechanical input. It will determine the structure and relationships of macromolecular complexes that, with deflections of the hair bundle, control the opening and closing of channels through which a current that triggers the neural stimulation flows. It will determine the organisation of the structural components within the supporting cells that create the rigid framework that is necessary to ensure that small vibrations from quiet sounds produce deflections of the bundle and signal detection. And it will define the pathway within a hair cell by which the chemical that is released to stimulate the nerve travels from where it is made at the top end of the cell to the bottom end. Abnormalities of the molecules associated with these activities cause hair cell dysfunction. Hair cell dysfunction and loss are the main causes of deafness and balance disequilibrium, major disabling conditions that are particularly prevalent in the elderly. By elucidating details of the relationships between structure and function, this project will contribute to understanding the fundamental bases underlying hair cell dysfunction. From such knowledge means to ameliorate the resultant physiological deficits -deafness and/or balance disequilibrium- will ensue.

大多数细胞功能依赖于相互作用分子的组装，以及这些复合物在细胞内的组织方式。此外，细胞本身被组织起来，将不同的活动划分到不同的区域，同时使这些活动能够整合，这是细胞发挥应有功能所必需的。因此，细胞结构和细胞功能之间存在非常密切的关系。因此，理解不同分子如何整合到细胞中以支持其功能，以及当疾病期间分子功能被破坏时细胞如何出错，至关重要的是在分辨率水平上了解三维细胞结构，从而能够可视化大分子组装体和它们正常发挥功能的细胞环境。电子显微镜揭示了从大分子的近似尺寸到整个细胞水平的结构细节。三维信息可以从组织切片检查电子显微镜通过应用现在建立的方法为“电子断层摄影术”。在这种技术中，从许多不同的角度拍摄相同结构的图像集合。当这些图像组合在一起时，获得了结构的三维视图。由此可以确定结构如何相互关联，例如一个分子复合物如何与另一个分子复合物相互作用，或者在较低的分辨率水平上，细胞内的细胞器如何分布以及它们之间是否存在连续性。如果组织是通过保存自然状态的方式准备用于显微镜检查的，这可以通过在处理之前非常快速地冷冻它们来实现，那么就有可能在细胞内的真实环境中获得接近生命条件下的亚细胞结构的细节。本项目将应用这些现代方法来评估内耳感觉组织的细胞结构特征。这些组织负责听觉和维持平衡，它们的结构非常三维。单个感觉“毛”细胞是圆柱形的，在它们的顶端有一束有组织的突起，突起的偏转响应于声音振动（听觉）或运动（平衡），导致向细胞底部的神经发出信号。每个毛细胞都被提供结构支持的细胞所包围。该项目将探索对细胞忠实地产生适当的神经输出以响应机械输入的能力至关重要的结构的组织。它将确定大分子复合物的结构和关系，这些复合物随着发束的偏转而控制触发神经刺激的电流流过的通道的打开和关闭。它将确定支撑单元内的结构组件的组织，该支撑单元创建刚性框架，该刚性框架对于确保来自安静声音的小振动产生束的偏转和信号检测是必要的。它将定义毛细胞内的通路，通过该通路，释放的化学物质刺激神经，从细胞的顶端到底端。与这些活动相关的分子的缺失导致毛细胞功能障碍。毛细胞功能障碍和损失是耳聋和平衡失调的主要原因，这是老年人特别普遍的主要残疾状况。通过阐明结构与功能之间关系的细节，该项目将有助于理解毛细胞功能障碍的基本基础。从这样的知识手段，以改善所产生的生理缺陷-耳聋和/或平衡不平衡-将随之而来。

项目成果

Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice.

塑蛋白1的缺失会导致毛细胞立体胶质的异常维持和小鼠的听力丧失形式。

• DOI: 10.1093/hmg/ddu417
• 发表时间: 2015-01-01
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Taylor R;Bullen A;Johnson SL;Grimm-Günter EM;Rivero F;Marcotti W;Forge A;Daudet N
• 通讯作者: Daudet N

Association of intracellular and synaptic organization in cochlear inner hair cells revealed by 3D electron microscopy.

• DOI: 10.1242/jcs.170761
• 发表时间: 2015-07-15
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Bullen A;West T;Moores C;Ashmore J;Fleck RA;MacLellan-Gibson K;Forge A
• 通讯作者: Forge A

Inner Hair Cell Membranes in ThreeDimensions: Links Between Membranes,Mitochondria and Vesicles

三维内毛细胞膜：膜、线粒体和囊泡之间的联系

• 发表时间: 2014
• 期刊: 37th Midwinter meeting of the Association for Research in Otolaryngology (ARO)
• 作者: Bullen A

Inner ear tissue preservation by rapid freezing: improving fixation by high-pressure freezing and hybrid methods.

• DOI: 10.1016/j.heares.2014.06.006
• 发表时间: 2014-09
• 期刊: HEARING RESEARCH
• 影响因子: 2.8
• 作者: Bullen, A.;Taylor, R. R.;Kachar, B.;Moores, C.;Fleck, R. A.;Forge, A.
• 通讯作者: Forge, A.