The overall goal of this proposal is to gain an understanding of the molecular mechanisms by which the pluripotency-maintaining transcription factor Oct4 induces proliferation while simultaneously maintaining an undifferentiated state in a cell-type specific manner in adult progenitor cells. We will address this question using a mouse model system harboring a doxycycline-inducible, Oct4 expressing transgene. Activation of this transgene in vivo rapidly results in hyperplasia in skin and intestinal stem cells, but has no discernable effect in other cell types. We will use gene array technology to identify Oct4 target genes and binding partners in the intestinal epithileum followed by stable, lentiviral-based RNA interference to determine the functional contribution of these target genes and coregulatory proteins to the hyperplastic phenotype observed in response to Oct4 activation. Validated Oct4 coregulatory factors will ultimately be introduced along with Oct4 into fibrobiasts (normally refractory to the pro-proliferative, anti-differentiative effects of Oct4) for the ultimate purpose of reactivating a state of pluripotency in differentiated somatic cells. This proposal will delineate molecular mechanisms that can potentially be manipulated to enhance regenerative medicine. ? ?
| Lengner, Christopher J; Camargo, Fernando D; Hochedlinger, Konrad et al. (2007) Oct4 expression is not required for mouse somatic stem cell self-renewal. Cell Stem Cell 1:403-15 |
