Heat shock transcription factor 1 (HSF1) and the stress response in the auditory system

Cells respond to stress by activating multiple signaling pathways, some of which result in enhanced cell survival and others lead to cell death. One of the best-characterized protective pathways involves the induction of the heat shock proteins (Hsps). Heat shock factor 1 (Hsf1) is one of the transcription factors responsible for regulating the stress-induced expression of genes for Hsps and certain other stress-responsive proteins. In the rodent cochlea, Hsp70 is upregulated in response to a number of stresses. For my dissertation, I have expanded on these previous studies by examining the role of Hsf1 in cochlear protection. Hsf1 is constitutively expressed in the normal rodent cochlea, where it is present in the outer and inner hair cells of the organ of Corti, in the stria vascularis, and in the spiral ganglion cells of the modiolus, consistent with the previously reported pattern of Hsp70 induction. Hsf1 is activated in the rodent cochlea in response to a physiologically relevant stress (hyperthermia) previously reported to precondition the cochlea against noise overstimulation. Examination of Hsf1 downstream targets revealed the presence of the actin regulatory protein, Hsp27, and the free radical scavenger, Hsp32, in the rodent cochlea. In the normal rodent cochlea, Hsp27 was present in the actin-rich outer hair cells and in the tension fibroblasts of the spiral ligament, while Hsp32 was only observed in scattered outer hair cells. Hsp32 levels were markedly upregulated in all three rows of outer hair cells and in the stria vascularis following the same heat shock that resulted in Hsf1 activation, suggesting a potential role for Hsp32 in cochlear protection. An Hsf1 deficient mouse model was used to directly investigate the role of Hsf1 in cochlear protection and recovery following stress. Mice lacking Hsf1 exhibited decreased recovery of hearing and increased outer hair cell loss following a moderate intensity noise exposure that in wild-type mice normally results in a fully reversible, temporary hearing loss. These studies provide evidence supporting an important role for Hsf1 and the Hsf1-dependent stress pathway in cochlear protection and recovery following stress in the rodent cochlea.