| Popis: |
The kinetics of the rate-limiting genes of the molecular DNA repair pathways of nucleotide excision repair (NER) were quantified from the inner ear as a function of cis-diamminedichloroplatinum-II (cisplatin) treatment. The distribution of the post-translational products of these genes was evaluated among neurons and sensory hair cells of the inner ear following cisplatin treatment. These NER factors (genes & post-translational products) are only potentiated by DNA damage and are particularly sensitive to cisplatin induced DNA damage. A 2 x 3 x 2 factorial design, consisting of two treatment conditions (saline and cisplatin treated Fischer344 rats), three survival times and two molecular analysis methods (polymerase chain reaction and immunohistochemistry) was employed in this dissertation. The results revealed at least five important findings. First, it revealed for the first time that complex DNA repair molecular pathways such as NER exist in the inner ear. Second, it revealed for the first time that molecules used by advanced tumor cells to detect and repair damaged DNA from cisplatin genotoxicity also generalize to the inner ear and are stimulated by even small sub-toxic doses of cisplatin. Third, it revealed for the first time that NER proteins reside in the cytoplasm of neurons under normal conditions and translocate to the nucleus under conditions of genomic stress. Fourth, it revealed for the first time that the basal coil of the mammalian cochlea differs from the apical coil in the magnitude and latency in which NER molecules translocate from the cytoplasm to the nucleus under conditions of genomic stress. Fifth, the current work provides the bases for a new line of hearing research focused on molecular mechanisms of inner ear DNA repair. |
