STRESS RESPONSE PATHWAYS IN THE RODENT COCHLEA

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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.