Molecular Mechanisms of Aminoglycoside Ototoxicity

氨基糖苷类耳毒性的分子机制

• 批准号: 10443277
• 负责人: Bo Zhao
• 金额: $ 56.87万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-07 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443277
• 关键词: Adverse effects; Adverse reactions; Affect; Aminoglycosides; Antibiotics; Antibodies; Area; Binding; Binding Proteins; Biochemical; Biochemistry; Biological Assay; Cell Death; Cell Survival; Cell physiology; Clinical; Cochlea; Data; Development; Dyes; Genes; Genetic; Gentamicins; Goals; Hair; Hair Cells; Human; Immunoblot Analysis; Immunofluorescence Immunologic; Infection; Knockout Mice; Label; Labyrinth; Life; Link; Mass Spectrum Analysis; Mediating; Methods; Mitochondria; Molecular; Morphogenesis; Multi-Drug Resistance; Mus; Mutation; Names; Organism; PINK1 gene; Parkin; Pathologic; Pathway interactions; Pharmacology; Physiological Processes; Prevention; Production; Proteins; Reactive Oxygen Species; Research; Role; Sensory Receptors; Signal Pathway; Stains; Testing; Yeasts; aminoglycoside-induced ototoxicity; base; hearing impairment; in vivo; insight; link protein; live cell imaging; mechanotransduction; mouse model; new therapeutic target; normal hearing; novel; novel strategies; ototoxicity; permanent hearing loss; prevent; protein function; response; screening; therapeutic development; yeast two hybrid system

PROJECT SUMMARY Aminoglycosides are widely used to treat serious infections, as they have good activity against many multi- drug resistant Gram-negative organisms. However, their strong and irreversible ototoxicity significantly limits their clinical usage. The overall goal of this research is to investigate the pathological mechanisms underlying AG ototoxicity and provide novel therapeutic targets to prevent it. We propose to investigate the functions of aminoglycoside-binding proteins in hair cells, the sensory receptors in the inner ear. In our preliminary studies, we have identified several proteins essential for aminoglycoside ototoxicity. Based on our preliminary data, we hypothesize that a novel pathological mechanism is involved in aminoglycoside ototoxicity. To test our hypothesis, we will: i) continue to investigate the expression, localization and functions of these proteins in hair cells; ii) continue to characterize mouse lines carrying mutations in these genes; iii) continue to investigate the functional interactions of these proteins in aminoglycoside ototoxicity. Our preliminary data show the feasibility of our approach. We anticipate that our studies will shed new insights into the molecular mechanisms underlying aminoglycoside ototoxicity and provide new leads for the development of new approaches to prevent aminoglycoside-induced hearing loss.

项目总结