Mitochondrial structure and non-syndromic and aminoglycoside-related deafness

线粒体结构与非综合征性和氨基糖苷类相关性耳聋

基本信息

批准号：
8638436
负责人：
ANNA LYSAKOWSKI
金额：
$ 25.14万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8638436
关键词：
Address Affect Aging Aminoglycoside Antibiotics Aminoglycosides Animals Antibiotics Apical Apoptosis Bioenergetics Cell Death Cell Nucleus Cell membrane Cells Cellular Structures Centrifugation Chemicals Cisplatin Cochlea Cochlear Implants Communities Connexins Disease Electron Microscope Elements Epithelium Exhibits Frequencies Genus Hippocampus Hair Cells Hearing Impaired Persons Huntington Disease Image In Vitro Laboratories Labyrinth Location Metabolic Mitochondria Mitochondrial Crista Mitochondrial Diseases Mitochondrial Proteins Molecular Muscular Dystrophies Mutation Noise Organ Organelles Outer Hair Cells Oxidative Phosphorylation Patients Population Positioning Attribute Preparation Proteins Publishing Rare Diseases Relative (related person)Research Respiration Respiratory Chain Role Sensory Stereocilium Stria Vascularis Structure Supporting Cell Therapeutic Time Tissues Toxic effect Variant Vestibular Hair Cells Vestibular Labyrinth assault cell injury chemotherapy deafness experience imaging modality interest nervous system disorder otoconia ototoxicity public health relevance respiratory response ribbon synapse tomography

项目摘要

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.

抽象的至少有十几种形式的线粒体相关耳聋（非合成和综合征形式以及氨基糖苷诱导的）和相关的前庭疾病。后连接蛋白相关的耳聋，线粒体相关的耳聋是第二常见的形式，负责所有后所有后耳聋的5％。仅一种形式的线粒体相关耳聋（A1555G突变）都存在于所有人工耳蜗植入患者中的一半以上由于氨基糖苷。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忽略了。线粒体形式的形式然而，耳聋与几种著名的神经系统疾病一样普遍，例如狩猎 - 吨，ALS或某些形式的肌肉营养不良。在体内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强烈的研究兴趣的话题。内耳中缺少这种结构研究的框架。该建议旨在填补通过研究整个动物和孤立的线粒体制剂中的毛细胞线粒体的间隙 - 为了解决线粒体相关的毛细胞损伤和细胞死亡的目的耳聋的形式。除了强调与线粒体相关的耳聋之外，我们认为这是建议值得考虑作为R21提案，因为我们将使用成像方法 - 在内耳场相对较新，研究内耳细胞中的线粒体细胞结构。我们还将将这些发现与我们预先的内耳线粒体的孤立亚群联系起来 DICE对耳毒性损伤的反应将有所不同，例如氨基糖苷或顺铂暴露。通过从该提案中获得的信息，治疗药可以更精确地针对线粒体呼吸链的特定部分在病态的毛细胞和因此，可以“营救”那些暴露于环境攻击的人（噪声，化学 PY，耳毒性抗生素）或衰老。