Physiology and Pathophysiology of Interactions between Hair Cells and Neurons.

 描述(申请人提供)：我的实验室的长期目标是阐明调节听觉感觉器官发育和功能的机制，以及内耳缺陷如何导致听力损失。我们建议研究免疫球蛋白超家族成员神经抑制素(NPTN)在内耳中的功能。根据我们的初步数据，我们假设NPTN通过初级NPTN转录本的选择性剪接来调节毛细胞的功能及其与感觉神经元的相互作用。为了验证我们的假设，我们将：(I)确定NPTN亚型在内耳中的表达模式和亚细胞定位；(Ii)研究NPTN亚型在毛细胞和内耳传入神经元中失活对听力功能的影响；(Iii)确定NPTN亚型在毛细胞和传入神经元中发挥功能的机制；(Iv)确定编码NPTN及其近似物的基因突变在多大程度上导致人类听力障碍。我们预计，我们的发现将揭示调控毛细胞及其神经感觉传入神经元功能的机制，以及NPTN突变如何导致疾病。

 DESCRIPTION (provided by applicant): The long-term goal of my laboratory is to elucidate the mechanisms that regulate the development and function of the auditory sense organ and how inner ear defects cause hearing loss. We propose here to study the function of the Ig-superfamily member neuroplastin (Nptn) in the inner ear. Based on our preliminary data we hypothesize that Nptn regulates hair cell function and their interactions with sensory afferent neurons by mechanisms that are regulated by alternative splicing of the primary Nptn transcript. To test our hypothesis, we will: (i) determine the expression pattern and subcellular localization of Nptn isoforms in the inner ear; (ii) Study the consequences of inactivation of Nptn isoforms in hair cells and afferent neurons of the inner ear for hearing function; (iii) Determine the mechanisms by which Nptn isoforms carry out their function in hair cells and afferent neurons; (iv) determine the extent to which mutations in the gene encoding NPTN and its close homologues cause hearing impairment in humans. We anticipate that our findings will reveal novel insights into the mechanisms that regulate the function of hair cells and their innervating sensory afferent neurons, and how mutations in NPTN cause disease.