Studies in cochlear hair cell transduction

描述（由申请人提供）：哺乳动物的耳朵包含两种类型的感觉受体细胞，即内毛细胞（IHC）和外毛细胞（OHC）。IHC将听觉信息传递给大脑，而OHC则充当局部放大器，以增强对IHC的输入。如果没有OHC的功能，听力阈值会严重下降，对不同声音频率的选择性也会被有效地消除。OHC如何增强耳朵的反应是听力科学的核心问题之一。有两种相互竞争的理论。在一种情况下，假设毛细胞的输入细胞器，即所谓的静纤毛，是能动的，并将能量反馈给它们所嵌入的振动系统，从而增强反应。另一种理论是基于OHC改变其长度以响应其电状态的变化的观察。这些长度的变化是由一种新的分子马达介导的，普雷斯廷，我们在五年前发现了它。这两种理论都有一些实验支持，但都有弱点。本研究的主要目的是建立OHC的放大模式，从而调和这两种理论。实现这一目标的主要方法是研究经工程改造表达普雷斯廷突变形式的小鼠的生理行为。换句话说，我们研究了在OHC中含有普雷斯廷分子但该分子无功能的动物的反应特征。因此，这些动物不具有能动的OHC，因此，所提出的扩增手段之一不存在，而另一种未改变。设计了额外的实验来检查普雷斯廷的分子性质，它可能是哺乳动物听力的关键分子。听力损失和耳聋，先天性或后天性的生活中，特别是在我们的老龄化人口中普遍存在，代表了最常见的公共卫生问题之一。这些缺陷的一个非常重要的部分涉及毛细胞，特别是OHC的退化或死亡。我们的全部努力都集中在解开OHC的属性及其在听力过程中的独特功能。

DESCRIPTION (provided by applicant): The mammalian ear contains two types of sensory receptor cells, inner hair cells (IHC) and outer hair cells (OHC). IHCs communicate auditory information to the brain, whereas OHCs function as local amplifiers to boost the input to IHCs. Without functioning OHCs, hearing threshold is severely degraded and selectivity to different sound frequencies is effectively eliminated. How OHCs boost the ear's response is one of the central issues of hearing science. There are two competing theories. In one, it is assumed that the input organelles of hair cells, so called stereocilia, are motile and feed energy back to the vibrating system in which they are embedded, thereby boosting the response. The other theory is based on the observation that OHCs change their length in response to changes in their electrical state. These length changes are mediated by a novel molecular motor, prestin, which we identified five years ago. Both theories have some experimental support and both have weaknesses. It is the principal aim of the present work to establish the mode of amplification by OHCs and thereby reconcile the two theories. The primary means of accomplishing this is to study the physiological behavior of mice engineered to express mutated forms of prestin. In other words, we examine response characteristics of animals that have the molecule prestin in their OHCs, but the molecule is non-functional. Thereby, these animals do not have motile OHCs and, consequently, one of the proposed means of amplification is absent, while the other is unaltered. Additional experiments are designed to examine the molecular nature of prestin, which may be the key molecule in mammalian hearing. Hearing loss and deafness, congenital or acquired during life, and especially prevalent in our aging population, represent one of the most common public health problems. A very significant fraction of these deficits involve deterioration or death of hair cells, especially OHCs. Our entire effort is focused on unraveling the properties of OHCs and their unique function in the hearing process.