Protection from Noise Induced Hearing Loss - Genetic and Drug Induction of HSPs

描述（由申请人提供）：拟议的研究解决了一个重大的健康问题，即由娱乐和工作场所相关活动以及在军队服役引起的噪音过度刺激引起的获得性耳聋的高发病率。在动物模型中，通过上调热休克蛋白（Hsps）激活经典应激反应在保护内耳免受噪声性听力损失方面非常有效。然而，临床应用的主要障碍是缺乏一种适当的方法来诱导人类内耳的热休克反应。我们提出了两种平行的方法来进一步评估热休克反应作为耳蜗噪声创伤的保护策略，并更接近一种有效的治疗方法。在一种方法中，我们将利用最近对激活HSF1分子的筛选结果，HSF1是热休克反应的主要调节因子。该筛选确定了一种化合物（HSF1A），它可以有效地激活已有的HSF1库，并导致靶热休克蛋白基因的上调。在神经退行性疾病的培养细胞和苍蝇模型中，HSF1的激活降低了蛋白质损伤和细胞毒性水平。我们的初步研究是首次对HSF1A在哺乳动物体内的疗效进行评估，并表明应用HSF1A可诱导耳蜗中热休克蛋白的上调。在第二种方法中，我们将研究热休克激活的另一种模式，通过产生转基因小鼠，在耳蜗中有条件地表达一种激活形式的HSF1 (HsfTgAct)，从而允许HsfTgAct的总体库暂时增加，并促进更强大的热休克反应。我们建议比较小分子和转基因方法在耳内激活热休克蛋白靶基因的效率，并评估它们的相对保护能力

DESCRIPTION (provided by applicant): The proposed studies address a significant health issue, the high incidence of acquired deafness from noise overstimulation that can result from recreational and workplace-related activities and from service in the military. Activation of the classic stress response by up-regulation of heat shock proteins (Hsps) has been very effective in protecting the inner ear from noise induced hearing loss in animal models. However, a major roadblock to clinical applicability is the lack of an appropriate method to induce the heat shock response in the inner ear in humans. We propose two parallel approaches to further evaluate the heat shock response as a protective strategy against noise trauma in the cochlea and move closer to an efficient therapeutic method. In one approach, we will exploit the findings of a recent screen for molecules that activate HSF1, the transcription factor that is the master regulator of the heat shock response. This screen identified a compound (HSF1A) that efficiently activates the pre-existing pool of HSF1 and results in up-regulation of target Hsp genes. This HSF1 activation reduces the levels of protein damage and cytotoxicity in cultured cell and fly models of neurodegenerative disease. Our preliminary studies were the first evaluation of the efficacy of HSF1A in vivo in the mammal and showed that application of HSF1A induces up-regulation of Hsps in the cochlea. In a second approach, we will investigate an alternative mode of heat shock activation through generation of transgenic mice that conditionally express an activated form of HSF1 (HsfTgAct) in the cochlea and thereby permit a temporary increase in the overall pool of HsfTgAct and promote a more robust heat shock response. We propose to compare the efficiencies of the small molecule and transgenic methods to activate HSP target genes in the ear and to evaluate their relative abilities to protect auditory function from noise trauma. These studies will take a critical step in moving a stalled therapeutic approach towards clinical application. Evidence of significant protection would provide justification for additional pre-clinical animal trials, a strong incentive for additional SF1 activator screens, and a route to testing efficacy in humans. An efficient method to activate the heat shock response in the inner ear could not only provide protection from noise-induced hearing loss for millions of people but would also have application to protection from ototoxins, affecting millions more.