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Lymphknotenmetastasierung nach Neck dissection bei Rezidiven oraler Plattenepithelkarzinome: Topographie und mögliche prognostische Parameter
Get PDFGeneration and functional characterization of induced pluripotent stem-cell-derived keratinocytes as an in-vitro model for Cockayne Syndrome, Xeroderma Pigmentosum and UV-sensitive Syndrome
Get PDFRecent progress in induced pluripotent stem-cell (iPS) research and genome editing has enabled the development of new approaches in clinical research for previously incurable diseases. Using these new technologies, I sought deeper understanding of a group of related diseases, namely Cockayne syndrome, xeroderma pigmentosum, and UV sensitive syndrome. The shared features in these diseases are their heredity aspect and the insufficiency of repair systems for DNA damage. The impairment of DNA repair systems leads to successive accumulation of genomic mutations, which often greatly elevate the risk of cancer and neuronal damage, and the skin’s sensitivity to ultraviolet (UV) light exposure. The specific differences among these related diseases are unknown. Effective therapies have also not yet been discovered. In this study, I used Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi), a method that can specifically and efficiently suppress genes of interest in undifferentiated and differentiated iPS cells. I developed a system to elucidate molecular mechanisms that
cause the specific characteristics of the diseases. For instance, when I suppressed ERCC6, a gene responsible for Cockayne syndrome, cell proliferation of iPS cells was impaired. A similar phenotype was observed using iPS cells generated from a Cockayne syndrome patient, suggesting that CRISPRi can reproduce the diseases’ phenotypes. This thesis will discuss differences and commonalities in phenotypes among the three diseases at the cellular and molecular levels. My work is based on suppressing the genes that are responsible for the diseases by testing iPS cells and iPS-cell-derived keratinocytes. Based on these findings new ideas for implication as therapy may be considerable, which I will
discuss at the end of this thesis
