Mitochondrial function and dysfunction in hair cells

毛细胞的线粒体功能和功能障碍

• 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
• 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

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.

项目总结