Studies in cochlear hair cell transduction

描述(申请人提供)：哺乳动物的耳朵含有两种感觉感受器细胞，内毛细胞(IHC)和外毛细胞(OHC)。IHC将听觉信息传递给大脑，而OHC则充当本地放大器，以增加IHC的输入。如果没有正常运作的神经细胞，听力阈值会严重下降，对不同声音频率的选择性也会有效地消除。毛细胞如何促进耳朵的反应是听力科学的中心问题之一。有两种相互矛盾的理论。在一种情况下，假设毛细胞的输入细胞器，即所谓的立体纤毛，是能动的，并将能量反馈给嵌入它们的振动系统，从而增强反应。另一种理论是基于观察到的OHC会随着其电状态的变化而改变其长度。这些长度变化是由一种新的分子马达Prestin介导的，我们在五年前发现了它。这两种理论都有一定的实验支持，也都有弱点。本工作的主要目的是建立OHC的扩增模式，从而调和这两种理论。实现这一点的主要方法是研究经过改造以表达突变形式的prestin的小鼠的生理行为。换句话说，我们检查了动物的反应特征，这些动物的内脏细胞中有Prestin分子，但该分子没有功能。因此，这些动物没有运动的毛细胞，因此，没有一种被提议的扩增手段，而另一种没有改变。还设计了其他实验来检查Prestin的分子性质，它可能是哺乳动物听力中的关键分子。听力损失和耳聋，无论是先天的还是后天的，在我们老龄化的人口中尤其普遍，是最常见的公共卫生问题之一。这些缺陷中有很大一部分涉及毛细胞的退化或死亡，特别是毛细胞。我们的全部工作集中在解开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.