Auditory Protein Regulation in Normal & Abnormal States

描述(申请人提供)：大约1%的美国人口是聋人，大约29.1%的65岁以上的人有听力损失问题。这些问题会导致所学语言的质量下降。这项提议的目标是以鸣禽为模型系统，识别与习得性发声的主动恶化有关的蛋白质。鸣禽是唯一可以研究人类语言基础--学习的声音交流的非人类动物之一。其他被普遍研究的动物没有这种能力。在鸣禽中，听到自己发声会导致听觉通路部分区域的基因和蛋白质表达大幅增加。这个表情被震耳欲聋的声音挡住了。发声的行为还会导致发声途径中基因和蛋白质表达的大幅增加。当鸟类像人类一样耳聋时，它们习得的发声能力就会恶化。鸣禽的这种退化是一个活跃的过程，涉及发声通路的基底节皮质样部分，在其中发现了发声驱动的基因表达。也就是说，为了防止完好动物的退化，它们需要通过听觉反馈听到自己的声音。到目前为止，很少有蛋白质被鉴定出具有这种感觉和运动驱动的调节，也没有被鉴定出随着耳聋导致的获得性发声恶化而发生变化的蛋白质。人们认为，在这些行为过程中，整个基因调控网络被激活。我们将使用行为学、神经解剖学和高通量蛋白质组学方法来鉴定和表征作为对照组的正常听力所激活的蛋白质和作为实验组的聋人导致的习得性发声退化所激活的蛋白质。由于大多数鸣禽蛋白与已知的哺乳动物蛋白具有显著的同源性，我们的实验将使我们能够在鸣禽系统中识别出与人类同源的鸟类脑蛋白。我们的长期目标是操纵这种蛋白质，以防止耳聋引起的嗓音恶化。

DESCRIPTION (provided by applicant): About 1% of the US population are deaf, and about 29.1% over the age of 65 have hearing loss problems. These problems cause deterioration in learned speech. The goal of this proposal is to identify proteins involved in active deterioration of learned vocalizations, using songbirds as a model system. Songbirds are one of the only accessible non-human animals where learned vocal communication, the substrate for human language, can be studied. Other commonly studied animals do not have this ability. In songbirds, hearing oneself vocalize induces large increases of gene and protein expression in parts of the auditory pathway. The expression is blocked by deafening. The act of vocalizing also induces large increases of gene and protein expression in the vocal pathway. When birds are deafened, like humans, their learned vocalizations deteriorate. This deterioration in songbirds is an active process involving the basal ganglia cortical-like part of the vocal pathway, in which vocalizing-driven gene expression is found. That is, the prevention of deterioration in intact animals requires that they hear themselves vocalize by auditory feedback. To date, few proteins have been identified with such sensory- and motor-driven regulation and none have been identified that change with deafening-induced deterioration of learned vocalizations. It is believed that an entire gene regulatory network is activated in these behavioral processes. We will use behavioral, neuroanatomical, and high throughput proteomic approaches to identify and characterize proteins activated by normal hearing of oneself vocalize as a control group and by deafened-induced deterioration of learned vocalizations as an experimental group. Since most songbird proteins have significant homology to known mammalian proteins, our experiments will enable us to identify avian brain proteins with human homologues amenable to experimental characterization in the songbird system. Our long-term goal is to manipulate such proteins to prevent deafened-induced vocal deterioration.