Physiology and Pathophysiology of Interactions between Hair Cells and Neurons.

 描述（由申请人提供）：我实验室的长期目标是阐明调节听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。我们建议在这里研究免疫球蛋白超家族成员的neuroplastin（Nptn）在内耳的功能。基于我们的初步数据，我们假设，Nptn调节毛细胞的功能和它们与感觉传入神经元的相互作用的机制，由初级Nptn转录的选择性剪接调节。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亚型在内耳毛细胞和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Nptn亚型在内耳毛细胞和传入神经元中的表达模式和亚细胞定位。（iv）确定编码NPTN的基因及其近缘同源物中的突变导致人类听力损伤的程度。我们预计，我们的研究结果将揭示调节毛细胞及其支配感觉传入神经元功能的机制，以及NPTN突变如何导致疾病的新见解。

 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.