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和 功能，并确定这一过程中导致耳聋的缺陷。我们建议在这里识别和研究 与MYO7A在物理和功能上相互作用的蛋白质，因此调节其在毛细胞中的功能。 根据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， 调节对毛束黏附和肌动蛋白聚合至关重要的蛋白质的运输，并直接 控制机械转导。为了检验我们的假设，我们将：(I)定义调节 立体纤毛粘附性，重点是由PCDH15和GRP98组成的那些；(Ii)决定MYO7A如何 络合物调节立体纤毛长度，最初集中在我们定义的带有CAPZ的络合物上；(Iii) 具体说明MYO7A及其相互作用的蛋白质如何控制机械转导。我们的初步数据显示 我们方法的可行性。我们已经确定了与MYO7A和MYO7A相互作用的发束蛋白 调停其功能。我们预计MYO7A的一些新的互动伙伴将在 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.