The goal of the proposed research is to elucidate the molecular pathogenetic mechanism of maternally inherited aminoglycoside induced hearing impairment. Aminoglycoside ototoxicity is a major clinical problem. In the United States, almost 4 million courses of aminoglycoside antibiotics are administrated annually for infections. It is estimated that between 2 to 5 percent of patients treated with these drugs develop significant hearing loss. In the developing countries, the problem of ototoxic side effects is more acute due to the widespread use of these drugs. Aminoglycoside ototoxicity is a complex multifactorial disorder resulting from interaction between genetic and environmental factors. The aminoglycoside hypersensitivity is often maternally transmitted. Recently, the A1 555G mutation in the mitochondrial 12S rRNA gene has been identified as an inherited mutation that predisposes to amingolycoside ototoxicity. This mutation accounts for a significant portion of patients with aminoglycoside ototoxicity. However, numerous important questions remain unanswered regarding the molecular and biochemical basis for genetic susceptibility to aminoglycoside ototoxicity.We hypothesize that human mitochondrial 12S rRNA, particularly that canying the A1555G mutation, is the main target of aminoglycosides and that these drugs exert their detrimental effects in the cochlea through an alternation of mitochondrial protein synthesis. We also hypothesize that there are additional mtDNA mutations associated with aminoglycoside ototoxicity. To test these hypotheses, we propose the specific aims as follows: 1) Examination of the binding of these drugs to the decoding site of mitochondrial 12S rRNA. 2). Examination of the mitochondrial specificity and dosage effect on these antibiotics by analysis of growth properties and rate of mitochondrial protein synthesis in A1555G mutation disease cell model. 3) Identification and evaluation of additional mtDNA mutations associated with aminoglycoside ototoxicity by a systemic and extended screening of a large Chinese clinical patient population with aminoglycoside ototoxicity.Success of this project will provide new insight into the pathogenic mechanisms of aminglycoside-associated ototoxicity, which in turns provide valuable new information and technology for the diagnosis and prevention of this disorder. The data from this study will help to predict which individuals are at risk for ototoxicity, improve the safety of clinical implications for the aminoglycoside-antibiotc therapy, and decrease the incidence of deafness. The ultimate goal of this study is to develop the aminoglycoside analogs with less toxicity and to provide aminoglycoside treatment strategies that prevent irreversible cochlear damage.
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