Control of Somatic Stem Cell Proliferation by Oct4

描述（由申请人提供）：本提案的总体目标是了解多能性维持转录因子Oct4诱导增殖同时以细胞类型特异性方式在成体祖细胞中维持未分化状态的分子机制。我们将解决这个问题，使用小鼠模型系统窝藏强力霉素诱导，Oct4表达转基因。这种转基因在体内的激活迅速导致皮肤和肠干细胞的增生，但对其他细胞类型没有明显的影响。我们将使用基因阵列技术，以确定Oct4的靶基因和结合伴侣在肠上皮细胞，然后通过稳定的，基于慢病毒的RNA干扰，以确定这些靶基因和共调节蛋白的功能的贡献，观察到的增生表型响应Oct4激活。验证的Oct4共调节因子将最终与Oct4一起沿着被引入成纤维细胞（通常对Oct4的促增殖、抗分化作用不敏感），最终目的是重新激活分化的体细胞中的多能性状态。这项建议将描绘分子机制，可以潜在地被操纵，以加强再生医学。

DESCRIPTION (provided by applicant): 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.