Mechanisms of Sensory Hair Cell Survival and Death

我们的基础科学研究主要集中在毛细胞应激时激活的信号转导和细胞间通讯途径。 我们先前研究了热休克蛋白（HSP）在促进应激条件下毛细胞存活中的作用。我们表明HSP诱导是内耳中的关键应激反应，其可以保护毛细胞免受主要应激，包括暴露于两种主要类别的耳毒性药物（即，氨基糖苷类抗生素和顺铂）。 我们发现，HSP表达的促生存诱导在毛细胞中相对较低，而在支持细胞和耳蜗驻留巨噬细胞中更强大。 这些数据表明，毛细胞可能有一个降低的能力，以诱导自主促生存信号在应激反应，并支持细胞和巨噬细胞的非自主信号作为促生存信号的关键介质时，毛细胞处于应激状态。 今年，我们仔细研究了耳蜗巨噬细胞作为内耳应激反应调节因子的作用。我们已经使用了巨噬细胞消融方法来测试巨噬细胞在顺铂诱导的毛细胞死亡和听力损失的背景下发挥的作用。我们的数据揭示了耳蜗巨噬细胞作为顺铂耳毒性介质的新作用，并且他们表明巨噬细胞可能有助于调节血液迷路屏障的渗透性，该屏障限制血液传播分子进入内耳。描述这些数据的手稿即将准备好提交。 我们的转化研究包括临床前实验，旨在开发治疗方法，以保护暴露于耳毒性药物或其他毛细胞应激的人类的听力。 我们之前已经证明，FDA批准的降胆固醇药物洛伐他汀可以降低顺铂诱导的小鼠听力损失，我们使用另一种同类药物阿托伐他汀复制了这一发现。这些数据表明，他汀类药物是一类有潜力保护接受顺铂救命抗癌治疗患者听力的药物。 我们的临床研究目前集中在确定他汀类药物在多大程度上减少顺铂诱导的人类听力损失。我们之前研究表明，接受顺铂治疗头颈部癌症同时服用阿托伐他汀的受试者与未服用他汀类药物的受试者相比，顺铂诱导的听力损失的发生率和严重程度降低（费尔南德斯et al 2021 PMCID：PMC7773379）。基于这些数据，我们启动了一项随机、安慰剂对照研究，以确定阿托伐他汀在多大程度上降低这一人群中顺铂诱导的听力损失。 今年沿着我们的合作者，我们收到了NIH U01，以支持这项多中心研究。 此外，目前正在与几所大学和合作政府机构合作开发一个大型患者听力图数据库，这将使我们能够更深入地研究他汀类药物使用与顺铂引起的听力损失之间的关系。这一资源也将使我们和其他人能够研究有关药物和听力损失之间关系的其他问题。

Our basic science studies are focused on the signal transduction and intercellular communication pathways that are activated in response to hair cell stress. We previously examined the roles of heat shock proteins (HSPs) in promoting survival of hair cells under stress. We showed that HSP induction is a critical stress response in the inner ear that can protect hair cells against major stresses, including exposure to both major classes of ototoxic drugs (i.e., the aminoglycoside antibiotics and cisplatin). We showed that pro-survival induction of HSP expression is relatively low in hair cells and is more robust in supporting cells and cochlear resident macrophages. These data indicate that hair cells may have a reduced capacity to induce autonomous pro-survival signaling in response to stress, and that non-autonomous signals from supporting cells and macrophages function as critical mediators of pro-survival signaling when hair cells are under stress. This year we have carefully examined the roles of cochlear resident macrophages as regulators of the inner ear responses to stress. We have used a macrophage ablation approach to test the roles macrophages play in the context of cisplatin-induced hair cell death and hearing loss. Our data reveal novel roles for cochlear macrophages as mediators of cisplatin ototoxicity, and they suggest that macrophages likely contribute to the regulation of the permeability of the blood-labyrinth barrier that restricts entry of bloodborne molecules into the inner ear. A manuscript describing these data is nearing readiness for submission. Our translational studies consist of preclinical experiments aimed at developing therapies to preserve hearing in humans exposed to ototoxic drugs or other hair cell stresses. We previously showed that the FDA-approved cholesterol-lowering drug lovastatin reduces cisplatin-induced hearing loss in mice, and we replicated that finding using another drug in the same class, atorvastatin. These data indicate that statins are a class of drugs that hold potential to protect the hearing of patients undergoing lifesaving anti-cancer treatment with cisplatin. Our clinical studies are currently focused on determining the extent to which statins reduce cisplatin-induced hearing loss in humans. We previously showed that subjects undergoing cisplatin therapy to treat head and neck cancer who are concurrently taking atorvastatin experience reduced incidence and severity of cisplatin-induced hearing loss compared to subjects not taking a statin (Fernandez et al 2021 PMCID: PMC7773379). Based on these data, we have initiated a randomized, placebo-controlled study to determine the extent to which atorvastatin reduces cisplatin-induced hearing loss in this population. This year along with our collaborators we received an NIH U01 to support this multi-site study. In addition are currently working with several universities and partner government agencies to develop a large database of patient audiograms that will allow us to more deeply examine the relationship between statin use and cisplatin-induced hearing loss. This resource will also allow us and others to examine additional questions about the relationships between medications and hearing loss.