MECHANISMS OF SENSORY REGENERATION

人耳感觉毛细胞的丧失是听力和平衡障碍的主要原因。虽然人类耳朵再生的潜力非常有限，但非哺乳类脊椎动物的耳朵在受伤后可以迅速再生。对这种修复过程的生物学基础的详细了解应该可以为促进人类类似形式的再生提供方法。本研究的总体目标是确定在再生过程中调节毛细胞表型和方向的生物信号。其中一个项目将专注于前庭毛细胞的分化。50多年来，人们已经知道高等脊椎动物的前庭器官含有两种不同的感觉毛细胞（称为I型和II型），但我们对这两种细胞的发育起源一无所知。使用这些细胞的新描述的标记物，我们将进行定量表征I型和II型毛细胞在再生过程中的恢复。第二个项目将研究毛细胞静纤毛如何在再生过程中重新获得正确的方向。我们已经发现，再生的毛细胞在器官培养的禽耳是正常的取向和我们的初步数据表明，平面细胞极性（PCP）信号通路的分子在这一过程中至关重要。一系列实验将使用体外方法直接测试PCP信号在再生中的作用。最后，我们将进行详细的研究，在哺乳动物耳蜗的核心PCP分子的表达变化后，耳毒性损伤。这些知识将是至关重要的所有目前的努力，旨在诱导哺乳动物内耳的生物修复。

The loss of sensory hair cells from the human ear is a leading cause of hearing and balance disorders. Although the potential for regeneration in the human ear is very limited, the ears of nonmammalian vertebrates can quickly regenerate after injury. A detailed understanding of the biological basis of this repair process should suggest methods for promoting similar forms of regeneration in humans. The overall goals of this study are to identify the biological signals that regulate hair cell phenotype and orientation during regeneration. One project will focus on the differentiation of vestibular hair cells. It has been known for over 50 years that the vestibular organs of higher vertebrates contain two distinct classes of sensory hair cell (which are known as type I and type II), yet we know nothing about the developmental origin of these two cell classes. Using newly-described markers for these cells, we will carry-out a quantitative characterization of the recovery of type I and type II hair cells during regeneration. A second project will examine how hair cell stereocilia reacquire their proper orientation during regeneration. We have found that regenerated hair cells in organ cultures of the avian ear are normally-oriented and our preliminary data suggest that molecules of the planar cell polarity (PCP) signaling pathway are critically involved in this process. A series of experiments will use in vitro methods to directly test the role of PCP signaling in regeneration. Finally, we will carry-out a detailed study of changes in the expression of core PCP molecules in the mammalian cochlea after ototoxic injury. Such knowledge will be crucial to all current efforts aimed at the induction of biological repair in the mammalian inner ear.