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

描述（由申请人提供）：大约35%的美国人有平衡问题，如眩晕、缺乏协调的运动和头晕。平衡问题会严重降低生活质量，增加高昂的医疗费用，并导致因跌倒而过早死亡。平衡性障碍的一个主要原因是内耳前庭毛细胞的丧失，这些细胞将头部运动转化为电信号，并通过前庭神经发送到大脑。毛细胞死亡的原因有很多，包括基因突变、损伤、感染、治疗性手术和药物治疗以及衰老。该项目汇集了两位研究者的专业知识，他们有以下目标：了解前庭毛细胞功能的基本机制，并开发治疗由毛细胞损伤或丧失引起的平衡障碍的方法。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——具有一种从未被描述过的特征：细胞质（或过程）的一个或多个延伸，从细胞基部向外侧突出，有时跨越几个细胞长度。这些突起具有多种形状，似乎与上皮中的其他细胞（包括其他II型毛细胞）接触。后一种观察提出了一种新颖的观点，即类型之间的直接交流

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.