Mitochondrial function and dysfunction in hair cells

毛细胞的线粒体功能和功能障碍

基本信息

批准号：
9215463
负责人：
David W Raible
金额：
$ 33.82万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9215463
关键词：
Affect Aminoglycoside Antibiotics Animal Model Biogenesis Body Surface Calcium Cause of Death Cell Death Cell physiology Cellular Metabolic Process Clustered Regularly Interspaced Short Palindromic Repeats Communication Coupling Cues Data Development Drug usage Endoplasmic Reticulum Fishes Functional disorder Future Genes Genetic Growth Hair Cells Hearing problem Human Human Genetics Image Imagery In Situ Labyrinth Light Measures Mechanical Stimulation Mechanics Metabolism Methodology Mitochondria Mitochondrial Diseases Mitochondrial Proteins Modeling Mutation Nuclear Orthologous Gene Pharmaceutical Preparations Pharmacology Play Process Regulation Reporter Role Sensorineural Hearing Loss Stimulus Stress Synaptic Transmission Syndrome System Testing Therapeutic Work Zebrafish experimental study genetic manipulation genome editing hearing impairment in vivo in vivo imaging lateral line mitochondrial metabolism ototoxicity oxidation response water flow

项目摘要

PROJECT SUMMARY Genetic disruptions of over thirty genes affecting mitochondrial functions result in hearing loss. We propose to understand the cellular consequences of representative mutations in mechanosensory hair cells. Our preliminary studies demonstrate that hair cells undergo rapid mitochondrial biogenesis as they mature, and that mitochondria actively respond to mechanosensory cues. We propose studies to understand the regulation of mitochondrial growth and function, focusing on the roles of specialized connections between mitochondria and the endoplasmic reticulum (ER). Growing evidence supports a role for ER-mitochondrial junctions regulating mitochondrial metabolism, dynamics, and stress and for playing a central role in regulated cell death. We propose experiments using live imaging of hair cells in the zebrafish lateral line, a system amenable to study of cellular functions in vivo. We will assess mitochondrial growth, oxidation and ATP utilization in hair cells, and determine the consequences of disrupting ER-mitochondrial communication. We will measure changes in mitochondria in response to mechanical stimuli. Using CRISPR, we will generate zebrafish models of human mitochondrial mutations to assess functional consequences for hair cells. Our experiments will reveal potentially fundamental mechanisms of mitochondria in hair cells and how these mechanisms go awry in human hearing loss.

项目摘要影响线粒体功能的三十多个基因的遗传破坏导致听力丧失。我们建议了解机械感觉毛细胞中代表性突变的细胞后果。我们的初步研究表明，毛细胞在成熟时会经历快速的线粒体生物发生，并且线粒体积极响应机械感应提示。我们建议研究以了解法规线粒体生长和功能，重点介绍线粒体之间的专业连接的作用和内质网（ER）。越来越多的证据支持ER-线粒体连接的作用调节线粒体代谢，动力学和压力，并在调节细胞死亡中发挥核心作用。我们建议使用斑马鱼侧线中毛细胞的实时成像进行实验，该系统可容纳研究体内细胞功能的研究。我们将评估头发的线粒体生长，氧化和ATP利用率细胞，并确定破坏ER-线粒体通信的后果。我们将衡量线粒体响应机械刺激的变化。使用CRISPR，我们将生成斑马鱼人线粒体突变的模型，以评估毛细胞的功能后果。我们的实验将揭示毛细胞中线粒体的潜在基本机制，以及这些机制如何进行人类听力损失有问题。