Genetic regulation of stem cell behavior in planarians

涡虫干细胞行为的遗传调控

• 批准号: 8771295
• 负责人: Nestor J Oviedo
• 金额: $ 35.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, MERCED
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8771295
• 关键词: AKT inhibition; Address; Adult; Affect; Alzheimer' s Disease; Animal Model; Animals; Apoptosis; Automobile Driving; Behavior; Behavior Control; Biological Models; Cancer Control; Cell Cycle; Cell Death; Cell Proliferation; Cells; Chemicals; Clinical; Degenerative Disorder; Diabetes Mellitus; Elements; Environment; Event; Future; Genes; Genetic; Goals; Growth; Guided Tissue Regeneration; Human; In Situ; Injury; Investigation; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Analysis; Natural regeneration; Normal Cell; Organism; Physiological; Physiology; Planarians; Platyhelminths; Process; Protein Kinase; Proto-Oncogene Proteins c-akt; RNA Interference; Regenerative Medicine; Regulation; Repair Complex; Research; Role; Signal Pathway; Signal Transduction; Sirolimus; Stem cells; Testing; Therapeutic; Tissues; Translating; Whole Organism; adult stem cell; aged; base; blastema; cell behavior; cell growth; design; genetic profiling; in vivo; inhibitor/antagonist; injury and repair; innovation; insight; interdisciplinary approach; migration; novel therapeutic intervention; progenitor; public health relevance; regenerative; repaired; response; response to injury; senescence; sensor; stem cell differentiation; stem cell therapy; tissue regeneration; tissue repair; transcriptomics; tumor progression

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.

描述（由申请人提供）：本项目的目标是通过在成人身体的复杂性中对AKT-TOR信号传导轴进行分子操纵来鉴定控制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，目前无法合理地控制SC在体内的行为严重限制了有效的基于SC的治疗的实施。SC调节的过程在很大程度上是未知的，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纵为控制体内SC行为提供了巨大的潜力。然而，这种方法需要充分表征SC在其自然环境中的调节。该项目使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）天然传感器：AKT-TOR轴，一种进化上保守的信号通路，整合了对细胞和生物体生理学至关重要的局部和系统信息，以及2）模型系统：扁形虫Schmidtea meditalienea，其具有非凡的再生能力和丰富的成体干细胞（成新细胞），所述成体干细胞可用于进化上保守的信号通路的分子分析。所提出的方法提供了一个优雅的，简化的和高度创新的模型，系统的调查SC过渡到分化和SC响应损伤和生理细胞周转。该项目是基于一个全面的跨学科的方法，研究SC在整个生物体的复杂性，考虑到本地和系统的内源性信号，调节他们的行为。它在评估组织再生和细胞更新过程中的成体SC调节方面是独一无二的。该策略的目的是在细胞周转和再生过程中，在操纵控制其行为的内源性信号后，跟踪体内新生细胞的反应。目的1将评估在缺乏TOR信号传导的情况下的再生过程，其特征在于缺乏再生芽基和组织重塑。TOR功能将在RNA干扰（RNAi）或特定化学抑制剂的作用下在完整的成年人中被废除。目的2将确定在AKT缺乏的情况下，通过用RNAi和抑制剂治疗废除完整成人中的AKT功能，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制细节。这些结果将为成人中AKT-TOR轴对SC的调节作用提供系统分析。该项目利用了细胞信号传导途径，这是许多控制癌症和退行性疾病的药理学方法的重点。预期未来的研究将转化为脊椎动物模型，并最终转化为临床再生医学。