Structural organisations underlying auditory sensitivity

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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.