Functions of Myosin VII in Mechanosensory Hair Cells

项目摘要 我们实验室的长期目标是阐明控制毛细胞发育的机制， 功能，并确定在这个过程中的缺陷，导致耳聋。我们在此建议， 这些蛋白质在物理和功能上与MYO7A相互作用，因此介导其在毛细胞中的功能。 基于已发表的和初步的数据，我们假设MYO7A在毛细胞中具有三重功能， 调节对毛束粘附和肌动蛋白聚合至关重要的蛋白质的转运， 控制机械传导。为了验证我们的假设，我们将：（i）定义介导 静纤毛粘附，重点是那些组成的PCDH 15和GRP98;（ii）确定MYO7A如何 复合物调节静纤毛长度，最初集中在我们定义的CAPZ复合物上;（iii） 说明MYO7A及其相互作用蛋白如何控制机械转导。我们的初步数据显示 我们的方法的可行性。我们已经鉴定出与MYO7A相互作用的毛束蛋白， 调节其功能。我们预计MYO7A的一些新的相互作用伙伴将受到影响， 导致听力障碍的遗传性疾病。

Project Summary The long-term goal of our laboratories is to elucidate the mechanisms that control hair cell development and function, and ascertain the defects in this process that cause deafness. We propose here to identify and study proteins that physically and functionally interact with MYO7A and therefore mediate its function in hair cells. Based on published and preliminary data, we hypothesize that MYO7A has a three-fold function in hair cells, regulating the transport of proteins critical for hair bundle adhesion and actin polymerization and directly controlling mechanotransduction. To test our hypothesis, we will: (i) define the protein complexes that mediate stereocilia adhesion, focusing on those consisting of PCDH15 and GRP98; (ii) determine how MYO7A complexes regulate stereocilia length, focusing initially on the complex with CAPZ that we have defined; (iii) specify how MYO7A and its interacting proteins control mechanotransduction. Our preliminary data show the feasibility of our approach. We have already identified hair bundle proteins that interact with MYO7A and mediate its function. We anticipate that some of the novel interaction partners of MYO7A will be affected in genetic diseases that cause hearing impairment.