The evolutionary success of transposable elements (TEs) is underscored by the finding that about 45% of the human genome is TE-derived. However, recent high throughput approach studies indicate that the impact of TE-associated activities was seriously underestimated. The first objective is to investigate the impact of TE-derived activities on the human genome in general and on disease mechanisms in particular, based on the central premise that some of these activities are stress-induced. To model how a vertebrate-specific transposon responds to stress signals in human cells, I will study molecular interactions of the Sleeping Beauty (SB) transposon with host cellular mechanisms to understand how stress-signalling and response triggers transposon activation. My second aim is to decipher the relationship between stress-induced activation of endogenous TEs and TE-derived regulatory sequences and human disease. I aim at investigating conditions and the consequences of activation of a particular copy of the MERmaid transposon located in the Sin3B transcriptional corepressor, frequently observed in cancer. The impact of global epigenetic remodelling will be investigated in the model of a complete (induced pluripotency) and partial (trans-differentiation) epigenetic reprogramming. In parallel, I aim at translating experience accumulated in TE research to cutting-edge technologies. First, the SB transposon will be adopted as a safe, therapeutic vector to treat age-dependent blindness (AMD). Second, a mutagenic SB vector will be used in a forward genetic screen to decipher a genetic network that protects against hormone-induced mammary cancer. The anticipated output of my research programme is a refined understanding of the consequences of environmental stress on our genome mediated by TE-derived sequences. The project is expected to provide an effective bridge between basic research and clinical- as well as technological translation of a novel gene transfer technology.