Thiamine Deficiency and Acquired Auditory Neuropathy

描述（由申请人提供）：听神经病（AN）是一种耳聋类型，其特征是尽管有强大的耳声发射，但仍缺乏听觉脑干反应，表明外毛细胞完好无损，而内毛细胞（IHC）和/或传入神经元功能障碍。AN表型可以是遗传性的或获得性的。早产是人类人群中获得性AN的重要危险因素，并且在动物模型中，AN也可以由耳毒性抗癌药物卡铂产生。我们实验室最近的两项观察结果表明，硫胺素缺乏可能是早产儿和卡铂治疗中选择性IHC丢失的关键，因此也是获得性AN的关键：1）早产儿中选择性IHC丢失的发生率惊人，2）在缺乏关键转运基因的小鼠中，IHC对硫胺素（维生素B1）缺乏具有独特的脆弱性。使用动物模型和尸检获得的人类颞骨，我们将测试以下假设：1）新生儿IHC的独特脆弱性是由于内耳中关键硫胺素转运蛋白基因的表达的迟发性而产生的，2）妊娠晚期或出生后早期的硫胺素缺乏可导致其他健康小鼠的选择性IHC丧失，和3）在卡铂治疗期间补充硫胺素可以挽救产生AN的IHC损失。 如果这些新的假设联系得到验证，基于硫胺素补充的简单疗法可能安全有效地降低新生儿重症监护室婴儿和接受铂类药物抗癌治疗的儿童或成人的听力损失患病率。

DESCRIPTION (provided by applicant): Auditory neuropathy (AN) is a type of deafness characterized by absence of auditory brainstem responses despite robust otoacoustic emissions, suggesting that outer hair cells are intact while inner hair cells (IHCs) and/or afferen neurons are dysfunctional. The AN phenotype can be either hereditary or acquired. Prematurity is an important risk factor for acquired AN in human populations, and, in animal models, AN can also be produced by the ototoxic anti-cancer drug, carboplatin. Two recent observations from our laboratory suggest that thiamine deficiency may be a key to the genesis of selective IHC loss, and therefore to acquired AN, in both prematurity and carboplatin therapy: 1) there is a striking prevalence of selective IHC loss in premature infants, and 2) IHCs have a unique vulnerability to thiamine (vitamin B1) deficiency in a mouse lacking a key transporter gene. Using animal models and human temporal bones obtained at autopsy, we will test the following hypotheses: 1) that the unique vulnerability of neonatal IHCs arises because of late-onset of expression of the key thiamine transporter genes in the inner ear, 2) that thiamine deficiency during late gestation or early post-natal life can cause selective IHC loss in otherwise healthy mice, and 3) that thiamine supplementation during carboplatin treatment can rescue the IHC loss that produces AN. If these novel hypothesized links are validated, simple therapies based on thiamine supplementation could be safe and effective in reducing the prevalence of hearing loss among infants in the neonatal intensive care unit and among children or adults undergoing anti-cancer therapies with platinum-based drugs.