Structure-function analyses on novel processes of type II vestibular hair cells

描述(由申请者提供)：大约35%的美国人经历过平衡问题，如眩晕、缺乏协调动作和头晕。平衡问题会严重降低生活质量，增加高昂的医疗费用，并因跌倒而导致过早死亡。平衡障碍的一个主要原因是内耳前庭毛细胞的丧失，它将头部的运动转化为电信号，通过前庭神经发送到大脑。毛细胞死亡的原因很多，包括基因突变、损伤、感染、治疗性手术和药物治疗以及衰老。这个拟议的项目汇集了两位研究人员的专业知识，他们有着共同的目标：了解前庭毛细胞功能的基本机制，并开发治疗毛细胞损伤或丢失导致的平衡障碍的方法。华盛顿大学(UW)的斯通实验室最近发现，成年啮齿动物的一种前庭毛细胞-II型-具有从未被描述的特征：一个或多个细胞质(或突起)从细胞底部横向伸出，有时超过几个细胞长度。这些突起有各种各样的形状，似乎与上皮中的其他细胞接触，包括其他类型的II型毛细胞。后一种观察结果提出了一种新的想法，即类型之间的直接交流 II毛细胞对前庭信号有调节作用。此外，Stone实验室发现，带突起的II型毛细胞是成年小鼠前庭上皮损伤后唯一能自发再生的毛细胞类型(Golub等人，2012年)。为了开发平衡障碍的治疗方法，确定自发再生的毛细胞的身份和它们在前庭加工中所起的作用是至关重要的。在这个项目中，威斯通大学的斯通实验室和哈佛大学的伊托克实验室提议对毛细胞过程进行表征，识别承载它们的毛细胞类型，并开始研究这些过程如何影响头部运动的编码和感觉信息从内耳到大脑的传输。对于正常和再生状态，斯通实验室将分析毛细胞与突起的形态和分子特性，而伊托克实验室将检查它们的生理特性，并定义这些突起与神经和其他毛细胞建立的连接类型。提出的对正常前庭器官的研究是确定新突起的结构及其在前庭加工中的功能的必要步骤。毛细胞-毛细胞通讯的确认将改变我们对毛细胞生物学的理解，因为它允许在视网膜中记录的横向相互作用的可能性。对受损前庭器官的研究将有助于揭示正常和再生毛细胞与突起之间的关系，以及再生毛细胞恢复平衡和听力障碍功能的潜力。

DESCRIPTION (provided by applicant): About 35% of Americans experience balance problems such as vertigo, lack of coordinated movements, and dizziness. Balance problems can severely reduce quality of life, add to high healthcare costs, and lead to premature death due to falls. A major cause of balance disorders is the loss of vestibular hair cells in the inner ear, which convert head movements into electrical signals that are sent to the brain via the vestibular nerve. Hair cell death has many causes, including gene mutation, injury, infection, therapeutic surgery and drug treatments, and aging. The proposed project brings together the expertise of two investigators who share the following goals: to understand the fundamental mechanisms underlying vestibular hair cell function and to develop ways to treat balance disorders resulting from hair cell injury or loss. The Stone lab at the University of Washington (UW) recently discovered that one type of vestibular hair cell - type II - in adult rodents has a feature that has never been described: one or more extensions of cytoplasm (or processes) that project laterally from the base of the cell, sometimes over several cell lengths. These processes have a variety of shapes and seem to contact other cells in the epithelium, including other type II hair cells. This latter observation raises the novel idea that direct communication between type II hair cells could modulate vestibular signaling. In addition, the Stone lab found that type II-lie hair cells with processes are the only hair cell type that is regenerated spontaneously in adult mouse vestibular epithelia after damage (Golub et al., 2012). In order to develop treatments for individuals with balance disorders, it is critical to define both the identity of spontaneously regenerated hair cells and the role that they play in vestibular processing. For this project, the Stone lab at UW and the Eatock lab at Harvard University propose to characterize the hair cell processes, to identify the hair cell type that bears them, and to begin to examine how these processes affect the coding of head movements and the transmission of sensory information from the inner ear to the brain. For both normal and regenerated states, the Stone lab will analyze morphological and molecular properties of hair cells with processes, while the Eatock lab will examine their physiological properties and define the types of connections that the processes make with nerves and other hair cells. Proposed studies in normal vestibular organs are essential steps in defining the structure of the novel processes and their functions in vestibular processing. Confirmation of hair cell-hair cell communication would transform our understanding of hair cell biology by allowing the possibility of lateral interactions as documented in the retina. Studies of damaged vestibular organs will help uncover the relationship between normal and regenerated hair cells with processes and the potential of regenerated hair cells to restore function in balance and hearing disorders.