Study of a genetic network involved in ear development

描述(申请人提供)：在此期间取得了巨大进展 过去五年在绘制和克隆负责 症状性和非症状性遗传性耳聋。这只老鼠是个极好的 用于研究这些人类状况的动物模型，因为解剖学， 耳朵的功能和遗传异常已被证明是相似的 在人类和老鼠身上都是如此。我们最近描述了一个这样的模型，结果是 来自杰克逊大学C3HIHeJ小鼠群体中的自发突变 实验室。反转录转座子(脑池内A粒子)插入 EYAL的一个内含子与正常EYA的表达减少相关] 消息和内耳及肾脏异常。我们已经指定了这个 这种基因的人类同源物EYAJ的突变EYA1已被证明 Branchio-Oto-Renal(B OR)综合征是一种常染色体显性遗传病 以听力损失为特征，伴有相关的鳃和肾异常。 人们对这种新的核蛋白的功能知之甚少。我们的 初步数据和我们的合作者的数据表明， 这个基因，以及这个基因家族的其他成员(EYAL-4)，在内耳 形态发生和出生后功能。 在这个提案中，我们打算探索埃亚尔参与的假设 一个调控网络，就像杰西在《果蝇眼》(Eya)中描述的那样，即 以剂量依赖的方式，对早期诱导是保守的和关键的 哺乳动物耳朵发育中的事件和成熟听觉的维持 表型。我们将检查对耳朵的剂量依赖效应和相关 在活体中，解剖、功能和分子上的结构。这将是 通过研究C3H/HeJ杂交产生的F1小鼠完成的 Eyalb0r/+和BALB/CJ Eya1+/-和EYAL过表达转基因突变体。 此外，我们将确定Eya同源区域(EyaHR)的区域 对与其他成员的蛋白质-蛋白质相互作用至关重要 这个保守的转录调控复合体。这些实验和未来的实验 代表了我指导的临床科学家的自然进步 发展奖(K08)。

DESCRIPTION (provided by applicant): Tremendous progress has been made during the last five years in the mapping and cloning of genes responsible for syndromic and nonsyndromic hereditary hearing loss. The mouse is an excellent animal model for the study of these human conditions because the anatomy, function and hereditary abnormalities of the ear have been shown to be similar in both humans and mice. We have recently described one such model resulting from a spontaneous mutation in a C3HIHeJ colony of mice at the Jackson Laboratory. The insertion of a retrotransposon (intracisternal A particle) into an intron of Eyal was associated with reduced expression of the normal Eya] message and inner ear and kidney abnormalities. We have designated this mutation Eya1 bor The human homologue of this gene, EYAJ, has been shown to underlie Branchio-Oto-Renal (B OR) syndrome, an autosomal dominant disorder characterized by hearing loss with associated branchial and renal anomalies. The function of this new class of nuclear protein is poorly understood. Our preliminary data, and that of our collaborators, suggests a critical role for this gene, and other members of this gene family (Eyal-4), in inner ear morphogenesis and postnatal function. In this proposal we intend to explore the hypothesis that Eyal participates in a regulatory network, as Jescribed in the Drosophila eye (eya), that is conserved and critical, in a dose dependent manner, to the early inductive events in mammalian ear development and maintenance of the mature auditory phenotype. We will examine the dose dependent effects on the ear and related structures, in viva, anatomically, functionally and molecularly. This will be accomplished by studying the Fl mice resulting from a cross between C3H/HeJ Eyalb0r/+ and BALB/cJ Eya1+/- and Eyal over-expression transgenic mutants. Additionally, we will identify the regions of the Eya homologous region (EyaHR) that are critical to the protein-protein interactions with other members of this conserved transcriptional regulatory complex. These and future experiments represent the natural progression from my Mentored Clinical Scientist Development Award (K08).