Mitochondrial structure and non-syndromic and aminoglycoside-related deafness

摘要 至少有十几种形式的与耳聋有关的耳聋（包括非综合征性耳聋和 综合征形式，以及氨基糖苷类诱导的）和相关的前庭疾病。后 连接蛋白相关性耳聋，尿道相关性耳聋是第二种最常见的形式， 造成了5%的语后耳聋这只是一种与尿道有关的耳聋 (the A1555 G突变）存在于超过一半的人工耳蜗植入患者中， 因为氨基糖苷类然而，大多数线粒体疾病被认为是“罕见”或“孤儿” 疾病，并在很大程度上被科学界所忽视。线粒体形式的 然而，耳聋与几种众所周知的神经疾病一样常见，例如，狩猎- 肌萎缩性侧索硬化症或某些形式的肌肉萎缩症。在身体的其他器官中， 线粒体及其在细胞凋亡和细胞死亡中的作用是一个具有强烈研究兴趣的主题。 这样的结构研究框架在内耳中缺失。该提案旨在填补 gap通过研究整个动物和分离的线粒体膜中的毛细胞线粒体， 目的是解决毛细胞损伤和细胞死亡的相关性 耳聋的形式。除了强调与心脏有关的耳聋，我们认为， 建议值得考虑作为R21建议，因为我们将使用成像方法- 对于研究内耳细胞线粒体精细结构的内耳领域来说，这是相对较新的技术。我们 还将这些发现与我们预先研究的内耳线粒体的分离亚群相关， dict对耳毒性损伤如氨基糖苷类或顺铂暴露的反应不同。 有了从这一建议中获得的信息，治疗可以更精确地针对 线粒体呼吸链的特定部分，在患病的毛细胞中受到损害， 因此，可以“拯救”那些已经暴露在环境攻击（噪音，化疗， py，耳毒性抗生素）或老化。

Abstract There are at least a dozen forms of mitochondrial-related deafness (both non-syndromic and syndromic forms, as well as aminoglycoside-induced) and associated vestibular disorders. After connexin-related deafness, mitochondrial-related deafness is the second most common form, responsible for 5% of all post-lingual deafness. Just one form of mitochondrial-related deafness (the A1555G mutation) is present in over half of all cochlear implant patients who become deaf due to aminoglycosides. Yet, most mitochondrial diseases are considered "rare" or "orphan" diseases, and have been largely ignored by the scientific community. Mitochondrial forms of deafness, however, are as common as several well-known neurological diseases, e.g., Hunting- ton's, ALS, or certain forms of muscular dystrophy. In other organs in the body, the structure of mitochondria and their role in apoptosis and cell death is a topic of intense research interest. Such a framework of structural studies is missing in the inner ear. This proposal aims to fill the gap by studying hair cell mitochondria in both whole animal and isolated mitochondrial prepara- tions for the purpose of addressing hair cell damage and cell death in mitochondrial-associated forms of deafness. Besides the emphasis on mitochondrial-related deafness, we think that this proposal merits consideration as an R21 proposal because we will be using imaging approach- es relatively new to the inner ear field to study mitochondrial fine structure in inner ear cells. We will also relate these findings to isolated sub-populations of inner ear mitochondria that we pre- dict will respond differently to ototoxic insults such as aminoglycoside or cisplatin exposure. With information gained from this proposal, therapeutics can be more precisely targeted toward specific parts of the mitochondrial respiratory chain that are compromised in ailing hair cells and can thus "rescue" those that have been exposed to environmental assaults (noise, chemothera- py, ototoxic antibiotics) or aging.