新转录复合物B98/P56调控神经祖细胞去分化过程的机制研究

The limited proliferative capacity of intermediate progenitors, or transit-amplifying cells, needs to be delicately restricted. The impairment of such regulation may result in dedifferentiation of progenitors back to a stem cell-like status. As a consequence, progenitors obtain self-renewal ability, proliferate in an uncontrolled manner, and transform into tumor-initiating cells, which eventually lead to tumorigenesis. Hence, understanding the fundamental mechanisms by which progenitor dedifferentiation is suppressed may shed new insights into selective elimination of tumor-forming stem cells and effective treatment of stem cell-derived cancer. In this project, we aim at utilizing Drosophila type II neural stem cells as an in vivo model system, combining with multiple approaches, in elucidating the molecular mechanisms by which Notch signaling modulates normal and tumor-initiating neural stem cells; demonstrating the interplay between a newly-identified transcription complex B98/P56 and Notch pathway; as well as suggesting novel strategies for selective eradiation of tumor-initiating cells. Upon successful completion of this project, we will provide new mechanistic insights into the suppression of dedifferentiation in transit-amplifying cells and new strategies for anti-cancer therapy.

祖细胞作为干细胞和终极分化细胞之间的过渡型细胞，其有限增殖及定向分化的能力受到极为精细、严格的调控。当调控发生紊乱，祖细胞可去分化，转变成和干细胞相似的、具有强大自我复制及分化能力的细胞，即肿瘤起始细胞，最终导致肿瘤的发生。因此，阐明祖细胞的去分化状态是如何被抑制的对于有针对性地清除肿瘤起始细胞及治疗干细胞衍生癌症有重要的借鉴意义。本项目将以果蝇幼虫II型神经干细胞作为模式，结合多种研究手段，重点研究Notch信号通路调控正常及肿瘤起始神经干细胞的分子机制，揭示新发现的转录复合物B98/P56在此调控过程中与Notch信号通路的互作关系，并探讨有选择性清除癌症起始干细胞的新方法。这项研究将有助于我们更深入地了解调控祖细胞去分化过程的分子机制，为干细胞衍生癌症的防治提供新的思路和理论依据。