Mechanisms of Sensory Hair Cell Survival and Death

感觉细胞生物学部分的研究重点是机械感觉毛细胞，它是听力和平衡的感受器细胞。感觉毛细胞将声音能量或头部运动转化为神经输入到大脑。毛细胞对各种压力引起的死亡很敏感，包括噪音创伤、衰老、某些基因突变，以及暴露在具有耳毒性副作用的治疗药物中。虽然毛细胞死亡之后是强劲的再生，恢复了非哺乳动物脊椎动物的听力和平衡功能，但在成熟的哺乳动物内耳中，毛细胞再生的能力极其有限。因此，哺乳动物的毛细胞死亡会导致永久性听力损失和/或平衡障碍。我们的基础科学研究旨在研究感觉毛细胞死亡和存活的机制。我们的翻译研究旨在利用这一机械知识来指导旨在预防或逆转人类听力损失的治疗的合理设计。 感觉细胞生物学部分目前正在研究两个主要问题： 1.决定毛细胞在压力下生存或死亡的细胞和分子信号是什么？ 2.我们如何将这些生存与死亡的信号转化为临床治疗，以防止听力损失？ 旨在解决第一个问题的研究集中在细胞应激的基础科学和对应激反应所激活的信号转导通路上。对应激信号的研究表明，应激下的细胞激活信号转导通路，从而促进细胞存活，同时激活促进细胞死亡的信号转导通路。通常正是这些死亡信号与生存信号的平衡(或失衡)决定了处于压力下的细胞最终是活着还是死了。我们的研究集中在毛细胞处于压力下时激活的死亡和生存信号。 目前，我们正在研究热休克蛋白(HSPs)在促进应激下毛细胞存活方面的作用。我们的研究表明，HSP诱导是内耳的一种关键应激反应，可以保护毛细胞免受主要应激的影响，包括暴露于两种耳毒性药物(即氨基糖苷类抗生素和顺铂)。重要的是，我们发现HSP表达的促生存诱导在毛细胞中相对较低，在周围的神经胶质样支持细胞中更为强劲(May等人，2013 J.临床调查123(8)：3577)。这些数据表明，毛细胞在应激反应中诱导支持生存信号的能力可能降低，当毛细胞处于应激状态时，支持细胞作为支持生存信号的关键中介发挥作用。 我们实验室正在研究的第二个主要问题是转化性的：我们如何开发促进毛细胞存活和功能的临床疗法，以保护暴露在耳毒性药物、噪音创伤或其他毛细胞压力下的人类的听力？为了实现这一目标，我们正在研究在耳蜗内诱导热休克蛋白的方法。我们使用药理HSP诱导剂雷公藤红素的数据表明，HSP诱导抑制了全身注射氨基糖苷类抗生素卡那霉素的小鼠中耳毒性药物引起的听力损失(Francis等人，2011年细胞死亡和疾病)。2，E195；doi：10.1038/cddis.2011.76)。 为了将热休克蛋白的诱导限制在内耳，我们最近研究了使用非创伤性声音暴露在耳蜗处诱导热休克蛋白的可行性。我们的数据表明，非创伤性的预适应声可以导致小鼠耳蜗热休克的诱导。重要的是，这种预适应声暴露可抑制全身给药顺铂或氨基糖苷类药物引起的听力损失和毛细胞死亡(Roy，Ryals等，2013 J.临床研究123(11)：4945)。这些数据表明，预适应声音可以保护内耳免受耳毒性药物所致听力损失的影响。声音疗法的一个优点是它不太可能引起全身副作用，也不会干扰顺铂或氨基糖苷类药物的治疗效果。我们目前正在开发一种策略，以测试预适应声音疗法是否可以保护接受耳毒性药物治疗的人的内耳。

Research in the Section on Sensory Cell Biology is focused on mechanosensory hair cells, which are the receptor cells of hearing and balance. Sensory hair cells transduce sound energy or head movement into neural input to the brain. Hair cells are sensitive to death from a variety of stresses, including noise trauma, aging, certain genetic mutations, and exposure to therapeutic drugs with ototoxic side effects. While hair cell death is followed by robust regeneration that restores hearing and balance function in non-mammalian vertebrates, the capacity for hair cell regeneration is extremely limited in the mature mammalian inner ear. Thus hair cell death in mammals results in permanent hearing loss and/or balance disturbances. Our basic science studies are designed to examine the mechanisms that underlie sensory hair cell death and survival. Our translational studies are designed to use this mechanistic knowledge to guide the rational design of therapies aimed at preventing or reversing hearing loss in humans. Two major questions are currently being studied in the Section on Sensory Cell Biology: 1. What are the cellular and molecular signals that determine whether a hair cell under stress lives or dies? 2. How can we translate these survival vs. death signals into clinical therapies to prevent hearing loss? Studies aimed at addressing the first question are focused on the basic science of cellular stress and the signal transduction pathways that are activated in response to stress. Studies of stress signaling suggest that cells under stress activate signal transduction pathways that will promote the cells survival while simultaneously activating pathways that will promote the cells death. It is often the balance (or imbalance) of these death vs. survival signals that determines whether the cell under stress ultimately lives or dies. Our studies are focused on the death and survival signals that are activated when hair cells are under stress. Currently we are examining the roles of heat shock proteins (HSPs) in promoting survival of hair cells under stress. Our studies demonstrate that HSP induction is a critical stress response in the inner ear that can protect hair cells against major stresses, including exposure to both classes of ototoxic drugs (i.e., the aminoglycoside antibiotics and cisplatin). Importantly, we find that pro-survival induction of HSP expression is relatively low in hair cells and is much more robust in surrounding glia-like supporting cells (May et al., 2013 J. Clinical Investigation 123(8):3577). These data indicate that hair cells may have a reduced capacity to induce pro-survival signaling in response to stress, and that supporting cells function as critical mediators of pro-survival signaling when hair cells are under stress. The second major question under study in our lab is translational: how do we develop clinical therapies that promote hair cell survival and function in order to preserve hearing in humans exposed to ototoxic drugs, noise trauma, or other hair cell stresses? Toward this goal we are examining methods of inducing HSPs in the cochlea. Our data using the pharmacological HSP inducer celastrol indicate that HSP induction inhibits ototoxic drug-induced hearing loss in mice receiving systemic injections of the aminoglycoside antibiotic kanamycin (Francis et al., 2011 Cell Death and Disease. 2, e195; doi:10.1038/cddis.2011.76). In order to restrict HSP induction to the inner ear, we have more recently examined the feasibility of using non-traumatic sound exposure to induce HSPs in the cochlea. Our data indicate that non-traumatic preconditioning sound can result in HSP induction in the cochleas of mice. Importantly, this preconditioning sound exposure inhibits hearing loss and hair cell death caused by systemic administration of either cisplatin or aminoglycosides (Roy, Ryals et al., 2013 J. Clinical Investigation 123(11):4945). These data indicate that preconditioning sound can protect the inner ear against ototoxic drug-induced hearing loss. An advantage of sound therapy is that it is unlikely to cause systemic side effects or to interfere with the therapeutic efficacy of either cisplatin or aminoglycosides. We are currently developing a strategy for testing whether preconditioning sound therapy can protect the inner ears of humans receiving ototoxic drugs.