Cytoskeletal dynamics in stereocilia maintenance

描述（由申请人提供）：进行性听力损失是一种常见的人类健康问题，通常源于内耳感觉毛细胞的丧失或功能障碍。肌动蛋白

DESCRIPTION (provided by applicant): Progressive hearing loss is a common human health problem that often stems from the loss or dysfunction of sensory hair cells in the inner ear. Actin proteins are central to hair cell structure and function; consequently, understanding the molecular mechanisms of cytoskeletal maintenance is a key step in considering rationally designed therapies for age-related or noise-induced hearing loss. ¿-Actin and ?-actin, two distinct yet closely related actin isoforms, each contribute to the population of filamentous actin in stereocilia. We have previously shown that mice with hair cells lacking either actin isoform form normal stereocilia, but go on to develop different forms of progressive hearing loss. This suggests that ¿-Actin and ?-actin each make unique contributions to stereocilia stability. This proposal is focused on two aspects of actin biology in stereocilia. In Aim 1, we will use existing conditional ¿-Actin and ?-actin knockout mouse lines and a newly developed transgenic actin reporter line to assess actin dynamics in stereocilia in vivo. In Aim 2, we will use cell biologica and biochemical approaches to determine if differential interactions between the actin bundling protein fascin 2 and ¿-actin and ?-actin contribute to distinct stereocilia maintenance mechanisms. Together, completion of these Aims will support a new model of actin regulation during stereocilia maintenance. In the long term, we will use the same suite of universal platforms established in this proposal to assess the roles of other deafness-causing mutant actin binding proteins in modulating stereocilia actin dynamics at the level of molecules, cells and mice.