STRESS RESPONSE PATHWAYS IN THE RODENT COCHLEA

细胞应激或创伤可诱导细胞内的“生存”途径，从而使细胞和系统 在应激和/或诱导细胞死亡的过程中，回到“正常”状态。 不同程度的压力会导致不同的途径。我们研究的长期目标是 制定干预措施，改变耳蜗应激反应中的平衡，使其转向导致保护、修复和恢复的途径，从而减少获得性耳聋。短期目标是确定耳蜗热休克蛋白(HSP)“保护性”途径的分子机制。第一个特定的目的是检查HSF1，调节HSP途径的转录因子(TF)是否被噪声以密切相关的方式激活，以及其他保护性或细胞死亡途径的转录因子何时被共同激活。第二个特定目的是通过确定HSF1基因敲除(KO)小鼠是否降低保护和/或从噪声中恢复，以及在HSF1过表达的转基因小鼠中是否增加保护，来测试HSF1-HSP途径在耳蜗中的保护作用。它还检查了HSF1KO小鼠是否仍然存在先前暴露在高温或噪音下的增强保护。第三个特定目的是检查HSF1途径中的下游靶标，并测试它们在KO小鼠耳蜗中的诱导及其与HSF1的关系。最终的特定目标是研究Hsp27，在Hsp27中，组成池的磷酸化已被证明通过调节肌动蛋白在其他系统中发挥保护作用。这些研究将增加对耳蜗热休克应激反应及其与其他保护和凋亡途径的相互作用的了解。它们将为未来研究减少获得性耳聋的干预措施提供一个合理的机制框架。

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.