STRESS RESPONSE PATHWAYS IN THE RODENT COCHLEA

细胞应激或创伤可以诱导细胞内的“生存”途径，使细胞和系统 在应激后恢复“正常”和/或诱导细胞凋亡途径以控制细胞死亡。 不同的压力水平可以诱导不同的途径。我们研究的长期目标是 制定干预措施，改变耳蜗压力反应的平衡，使之转向保护、修复和康复的途径，从而减少后天性耳聋。短期目标是确定耳蜗中“保护性”热休克蛋白（Hsp）通路的分子机制。第一个具体的目的是检查是否Hsf 1，转录因子（TF）调节热休克蛋白途径，被激活的噪音在一个密切依赖的方式，当TF的其他保护或细胞死亡途径被共激活。第二个具体目标是测试Hsf 1- hsp通路在耳蜗保护中的作用，通过确定Hsf 1敲除（KO）小鼠中是否存在降低的保护和/或从噪声中恢复，以及在Hsf 1过表达的转基因小鼠中是否存在增加的保护。它还检查了Hsf 1 KO小鼠中是否仍然存在对先前暴露于热或噪声的增强保护。第三个具体目标是检查Hsf 1通路中的下游靶点，并测试它们在KO小鼠耳蜗中的诱导以及与Hsf 1的关系。最后的具体目标检查热休克蛋白27，其中磷酸化的组成池已被证明在其他系统中发挥保护作用，通过调节肌动蛋白。这些研究将增加对耳蜗中hsp应激反应及其与其他保护性途径和凋亡途径的相互作用的理解。他们将产生一个合理的机制框架，为未来的研究干预措施，以减少后天性耳聋。

Cell stress or trauma can induce intracellular "survival" pathways that bring cells and systems back to "normal" following the stress and/or induce apoptosis pathways for controlled cell death. Different levels of stress can induce different pathways. The long-term goal of our studies is to develop interventions that can change the balance in the stress response of the cochlea towards the pathways that lead to protection, repair and recovery, thus reducing acquired deafness. The short-term goal is to determine the molecular mechanisms underlying the "protective" heat shock protein (Hsp) pathway in the cochlea. The first specific aim examines if Hsf1, the Transcription Factor (TF) regulating the Hsp pathway, is activated by noise in a close dependent fashion and when TFs for other protective or cell death pathways are co-activated. The second specific aim tests the role of the Hsf1 - hsp pathway in protection in the cochlea, by determining if there is decreased protection and/or recovery from noise in Hsf1 knock out (KO) mice and increased protection in transgenic mice with Hsf1 overexpression. It also examines if enhanced protection from prior exposure to heat or noise is still present in the Hsf1 KO mice. The third specific aim examines downstream targets in the Hsf1 pathway and tests their induction in the cochlea and relation to Hsf1 in the KO mice. The final specific aim examines hsp27, in which phosphorylation of the constitutive pool has been shown to play a protective role in other systems through regulation of actin. These studies will provide increased understanding of the hsp stress response in the cochlea and its interplay with other protective versus apoptotic pathways. They will generate a rational mechanistic framework for future studies on interventions to reduce acquired deafness.