The role of LRBA (LPS-responsive, beige-like anchor protein) in auditory function

LRBA （LPS-responsive， beige-样锚蛋白）属于BEACH蛋白家族，其成员参与细胞内蛋白运输和突触前和突触后功能。我们证实LRBA在内毛细胞和外毛细胞、螺旋韧带和血管纹边缘细胞中表达。通过听觉脑干反应（ABR）和惊吓反应评估，发现LRBA基因敲除小鼠有中度至重度听力损失。进一步的初步系统和细胞生理数据表明，毛细胞功能障碍结合了传导电流和突触传递的缺陷。为了进一步区分LRBA基因敲除小鼠的听力损失机制，我们计划记录不同年龄小鼠的abr，并测量耳蜗电位和内淋巴钾浓度。我们将研究幼年动物毛细胞立体纤毛的形态和fm1 -43摄取，并通过膜片钳实验评估毛细胞突触前功能，如果需要的话，还可以通过毛细胞转导电流和外毛细胞电运动性来评估。LRBA中断对听觉通路信号编码的影响将通过单听神经纤维记录和行为测试进行检验。我们的数据也将有助于更好地理解LRBA和BEACH蛋白的分子和细胞生物学功能。

LRBA (LPS-responsive, beige-like anchor protein) belongs to the BEACH protein family, members of which are involved in intracellular protein trafficking and in pre- and postsynaptic function. We demonstrated that LRBA is expressed in inner and outer hair cells, the spiral ligament, and in marginal cells of the stria vascularis. LRBA knockout mice were found to have moderate to severe hearing loss, as assessed by auditory brainstem responses (ABR) and startle responses. Further preliminary systems and cell physiological data suggest a hair cell dysfunction that combines a deficit of transduction currents and synaptic transmission. To further differentiate the mechanism of hearing loss in LRBA knockout mice, we plan to record ABRs at different mouse ages and to measure the endocochlear potential and endolymphatic potassium concentration. We will study the morphology and FM 1-43 uptake of hair cell stereocilia in young animals and assess inner hair cell presynaptic function by patch clamp experiments and, if needed hair cell transduction currents and outer hair cell electromotility. Effects of LRBA disruption on signal encoding in the auditory pathway will be examined both by single auditory nerve fiber recordings and by behavioral testing. Our data will also help to better understand the molecular and cell biological function of LRBA and of BEACH proteins in general.