Genetic regulation of stem cell behavior in planarians

描述(由申请人提供)：本项目的目标是通过对AKT-TOR信号轴的分子操纵，在成人身体的复杂性中识别控制SC行为的内源性机制。干细胞(SC)疗法为诱导因衰老、癌症或损伤而受损的组织再生提供了巨大的希望。然而，目前无法合理控制干细胞在体内的行为，严重限制了基于干细胞的有效治疗的实施。SC调节的过程在很大程度上是未知的，它涉及通过信号通路协调细胞行为的局部和系统信号。整合局部和系统信息的细胞信号通路的分子操作为控制体内SC的行为提供了巨大的潜力。然而，这种方法需要充分描述其自然环境中的SC法规。这个项目利用两个重要元素解决了基于SC的再生和修复的基本问题：1)一个自然传感器：AKT-TOR轴，一个进化上保守的信号通路，它整合了细胞和生物生理中的局部和系统信息；2)一个模型系统：扁平线虫Schmidta Medranea，它具有非凡的再生能力和丰富的成体干细胞(新生母细胞)，可以用于进化保守的信号通路的分子分析。该方法为系统地研究SC向分化的转变以及SC对损伤和生理细胞更新的反应提供了一种简洁、简洁和极具创新性的模型。该项目基于一种综合的跨学科方法，在整个有机体的复杂性中研究干细胞，同时考虑调节其行为的局部和系统内源性信号。它在评估成体干细胞在组织再生和细胞周转过程中的调节方面是独一无二的。该策略旨在跟踪体内新生细胞在控制其行为的内源性信号操纵后的细胞更新和再生过程中的反应。目的1将评估在没有TOR信号的情况下的再生过程，其特征是没有再生胚泡和组织重塑。在使用RNA干扰(RNAi)或特定化学抑制剂的完整成人中，TOR功能将被取消。目的2将通过用RNAi消除完整成人的AKT功能并用抑制剂治疗，来确定在缺乏AKT的情况下，新生细胞对组织修复机制的贡献。该项目的成功完成将提供祖细胞如何被指示修复复杂组织的机械细节。这些结果将为成人对AKT-TOR轴对干细胞的调节作用提供系统的分析。这个项目利用了细胞信号通路，这是许多控制癌症和退行性疾病的药理学方法的重点。预期的未来研究将转化为脊椎动物模型，并最终转化为临床再生医学。

DESCRIPTION (provided by applicant): The goal of this project is to identify endogenous mechanisms controlling SC behavior through molecular manipulation of the AKT-TOR signaling axis in the complexity of the adult body. Stem cell (SC) therapy offers great promise for inducing regeneration of tissue damaged by senescence, cancer or injury. However, the current inability to rationally control the behavior of SCs in vivo severely limits the implementation of effective SC-based treatment. The largely unknown process of SC regulation involves local and systemic signals that coordinate cellular behavior through signaling pathways. Molecular manipulation of cell signaling pathways that integrate local and systemic information offer great potential to control SC behavior in vivo. This approach, however, requires full characterization of SC regulation in their natural environment. This project addresses the fundamental problem of SC-based regeneration and repair using two important elements: 1) a natural sensor: the AKT-TOR axis, an evolutionarily conserved signaling pathway that integrates local and systemic information that is central to cellular and organismal physiology, and 2) a model system: the planarian flatworm Schmidtea mediterranea, which has extraordinary regenerative capacity and abundant adult stem cells (neoblasts) that are accessible for molecular analysis of evolutionarily conserved signaling pathways. The proposed approach provides an elegant, simplified and highly innovative model for systematic investigation of SC transition to differentiation and SC response to injury and physiological cell turnover. This project is based on a comprehensive interdisciplinary approach that studies SCs in the complexity of the whole organism considering both local and systemic endogenous signals that modulate their behavior. It is unique in assessing adult SC regulation during the process of tissue regeneration and cell turnover. The strategy is designed to follow neoblast response in vivo during cell turnover and regeneration after manipulation of endogenous signals that control their behavior. Aim 1 will assess the process of regeneration in the absence of TOR signaling, which is characterized by the absence of regenerative blastema and tissue remodeling. TOR function will be abrogated in intact adults with RNA-interference (RNAi) or specific chemical inhibitors. Aim 2 will determine neoblast contribution to tissue repair mechanisms in the absence of AKT by abrogating AKT function in intact adults with RNAi and treatment with inhibitors. Successful completion of this project will provide mechanistic details of how progenitor cells are instructed to repair complex tissues. These results will provide a systemic analysis in adults of the regulatory effects of the AKT-TOR axis on SCs. This project capitalizes on a cellular signaling pathway that is the focus of many pharmacological approaches to control cancer and degenerative diseases. Anticipated future studies will be translated to vertebrate models and ultimately to clinical regenerative medicine.