Thiamine Deficiency and Acquired Auditory Neuropathy

描述(申请人提供)：听神经病(AN)是一种耳聋，特征是尽管有强大的耳声发射，但没有听性脑干反应，表明外毛细胞完整，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，也可以是获得性的。早产是人类获得性AN的一个重要风险因素，在动物模型中，耳毒性抗癌药物卡铂也可以产生AN。我们实验室最近的两项观察表明，硫胺素缺乏可能是早产儿和卡铂治疗中选择性IHC丢失，从而导致获得性AN的关键：1)在早产儿中，选择性IHC丢失的发生率很高；2)在缺乏关键转运蛋白基因的小鼠中，IHC对硫胺素(维生素B1)缺乏具有独特的易感性。利用动物模型和尸检中获得的人类颞骨，我们将检验以下假设：1)新生儿IHC的独特脆弱性是由于关键的硫胺转运体基因在内耳中表达的延迟而产生的，2)妊娠后期或出生后早期的硫胺缺乏可导致其他健康的小鼠选择性IHC丢失，以及3)在卡铂治疗期间补充硫胺可挽救产生APC的IHC丢失。如果这些新的假设得到证实，基于硫胺素补充的简单疗法可以安全有效地降低新生儿重症监护病房中的婴儿以及接受铂类药物抗癌治疗的儿童或成人的听力损失发生率。

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.