Molecular Biology Laboratory
Research
The Molecular Biology Laboratory at the Kresge Hearing Research Institute studies the molecular mechanisms and biochemical pathways that underlie auditory function, using an array of molecular biological approaches. There are two main areas of research:
- Stress Pathways in Age-Related Hearing Loss
- Molecular Genetics of Acoustic Trauma and Response to Trauma in Mammals
Stress Pathways in Age-Related Hearing Loss
We have been examining the role of an important protective pathway, the heat shock or stress response, in young mice (Altschuler et al., 1999; Altschuler et al., 2002; Fairfield et al., 2002; Fairfield et al., 2004; Fairfield et al., 2005). The stress response is controlled by heat shock transcription factor 1 (HSF1), which controls the expression of genes for heat shock proteins. Heat shock proteens are known to protect many different organs and tissues from various environmental and physiological stresses. We showed that genetically engineered mice that lack HSF1 (Hsf1 knockout mice) are more sensitive to noise (Fairfield et al., 2005) and that the induction of this response decreases with age. We are testing the hypothesis that this decrease in an important protective pathway contributes to age-related hearing loss (presbycusis), a major health problem that affects the quality of life of the elderly. We are now examining the rate of age-related hearing loss in these mice as part of a collaborative research project supported by the National Institute on Aging. We are also beginning to develop mouse models in which the stress response is elevated, to determine whether or not higher levels of heat shock proteins can protect the inner ear from age-related hearing loss.
Publications
- Altschuler, R. A., Fairfield, D., Cho, Y., Leonova, E., Benjamin, I. J., Miller, J. M., and Lomax, M. I. (2002). Stress pathways in the rat cochlea and potential for protection from acquired deafness. Audiol Neurootol 7, 152-156.
- Altschuler, R. A., Miller, J. M., Raphael, Y., and Schacht, J. (1999). Strategies for protection of the inner ear from noise induced hearing loss. In Cochlear Pharmacology and Noise Trauma, D. K. Prasher, and B. Canlon, eds. (London, England, Noise Research Network Publications), pp. 98-112.
- Fairfield, D. A., Kanicki, A. C., Lomax, M. I., and Altschuler, R. A. (2002). Expression and localization of heat shock factor (Hsf) 1 in the rodent cochlea. Hear Res 173, 109-118.
- Fairfield, D. A., Kanicki, A. C., Lomax, M. I., and Altschuler, R. A. (2004). Induction of heat shock protein 32 (Hsp32) in the rat cochlea following hyperthermia. Hearing Research 188, 1-11.
- Fairfield, D. A., Lomax, M. I., Dootz, G. A., Chen, S., Galecki, A. T., Benjamin, I. J., Dolan, D. F., and Altschuler, R. A. (2005). Heat shock factor 1-deficient mice exhibit decreased recovery of hearing following noise overstimulation. J Neurosci Res 81, 589-596.
Molecular Genetics of Acoustic Trauma and Response to Trauma in Mammals
Cells and organs cope with traumatic changes in their environment by regulating gene expression. These changes in gene expression can provide a protective mechanism, a homeostatic return to "normal" and/or a controlled reaction to trauma. We hypothesize that such genetic mechanisms exist in the mammalian ear, specifically in its response to acoustic overstimulation leading to either temporary threshold shifts (TTS) or permanent threshold shifts (PTS). Our studies employ a new molecular genetic approach, gene arrays or DNA microarrays, to identify genes activated by either moderate or severe noise overstimulation in rats. We are currently determining whether these genes are involved in protecting the inner ear hair cells and the auditory nerve from programmed cell death, or are involved in activating the cell death pathway in either the organ of Corti or the auditory nerve.
Gene profiling of RNA from normal adult rat inferior colliculus and modiolus. Clontech. Block C of the Atlas Rat cDNA Expression Array from the Phosphorimager, a figure is shown above. Atlas Array membranes were hybridized with 32P-labeled cDNA synthesized from 2 mg total RNA according to the protocol. (Cho et al., 2001)
Publications
- Lomax, M.I., L. Huang, Y. Cho, T.-W. L. Gong, and R. A. Altschuler. Differential display and gene arrays to examine auditory plasticity. Hearing Research, 147:293-302, 2000.
- Lomax, M.I., T.-W.L. Gong, Y. Cho, L. Huang, S.H. Oh, H.J. Adler, Y. Raphael, and R.A. Altschuler: Differential gene expression following noise trauma in birds and mammals. Noise & Health, 11:19-35, 2001Stover, T., T.W.-L. Gong, Y. Cho, R.A. Altschuler, and M.I. Lomax: Expression of the GDNF family members and their receptors in the mature rat cochlea. Molecular Brain Research, 76: 25-35, 2000.
- Stover, T., T.W.-L. Gong, Y. Cho, R.A. Altschuler, and M.I. Lomax: Glial cell line-derived neurotrophic factor (GDNF) and its receptor complex are expressed in mature rat cochlea. Hearing Research, 155:143-151, 2001
- Leonova, E.V., Fairfield, D.A., Lomax, M.I. Altschuler, R.A. Constitutive expression of Hsp27 in the rat cochlea. Hearing Research, 163:61-70, 2002.
- Cho, Y., T.-W. L. Gong, T. Stover, M. I. Lomax, and R. A. Altschuler. Gene expression profiles in the rat auditory system. JARO 3:54-57.
- Cho, Y., R. A. Altschuler, M.I. Lomax. Noise overstimulation induces immediate early genes in the rat cochlea. In preparation.
- Kanzaki, S., Kawamoto, K., Oh, S.-H., Stover, T., Suzuki, M., Isimoto, S., Yagi, M., Miller, J. M., Lomax, M. I., Raphael, Y. From gene identification to gene therapy. Audiology Neurootology, 7:161-164, 2002.
- Altschuler, R.A., D.A. Fairfield, Y. Cho, E. Leonova, I.J. Benjamin, J.M. Miller, M.I. Lomax. Stress pathways in the rat cochlea and potential for protection from acquired deafness. Audiology Neurootology, 7:152-156, 2002.
- Leonova, E.V., and Lomax, M.I.: Expression of the mouse Macf2 gene during inner ear development. Molecular Brain Research, in press.
