Synthetic cell-based patterning systems and their applications in stem cell differentiation

基于细胞的合成图案系统及其在干细胞分化中的应用

• 批准号: 2645883
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2645883
• 关键词: Synthetic; cell; based; patterning; systems

he haematopoietic system serves as a paradigm for understanding cellular hierarchies and properties of tissue-specific stem cells. Haematopoietic and Leukaemic Stem Cells (HSCs, LSCs) constitute the pioneering models for understanding aspects of both physiological and malignant stem cell biology, making the bone marrow and blood the ideal models to study tissue repair and neoplasia. Albeit constituting the best characterized somatic and cancer stem cells respectively, there is still no clear understanding of the gene regulatory networks that regulate physiological haematopoiesis, and how these are corrupted during leukaemogenesis. I am most interested in dissecting the logic and the nature of these networks in haematopoiesis and how their constituent factors are affected by external conditions, such as niche-derived signals and particularly hypoxia. Characterizing such networks and/or the effect of extrinsic conditions shall substantially contribute in understanding HSC fate-decisions, which might provide insights into the expansion of HSCs ex vivo as well as into the underlying mechanisms of leukaemogenesis, whose hallmark is the deregulation of HSC fate-decisions.Understanding and recreating (or vice versa) a natural stem cell niche and/or tissue is an integral part of stem cell biology and regenerative medicine. Recreating the bone marrow niche might provide a steady platform to expand HSCs ex vivo. In theory, such synthetic system should provide a platform to study the biology of HSCs, a reliable method to generate sufficient HSC yields for curative transplantations, and an in vitro pharmacological screening system which can provide novel insights into targeting the LSC niche. Due to the tissue complexity of the bone marrow and given that synthetic morphology is a very young field, building and understanding simpler systems is of primary priority. To achieve this, I would be keen on i) investigating known genes in the induction of morphogenic modules, ii) link and coordinate specific modules into certain sequence and iii) establish a link between such modules and core principles of developmental biology (e.g. Turing's system). Such complex genetic engineering would be sufficient to generate, at least in theory, simply patterned tissues, but would also provide a platform to generate more complex morphogenesis.

造血系统是理解细胞层次结构和组织特异性干细胞特性的范例。造血干细胞和白血病干细胞(HSCs，LSCs)构成了了解生理和恶性干细胞生物学方面的开创性模型，使骨髓和血液成为研究组织修复和肿瘤形成的理想模型。尽管分别构成了最具特性的体细胞和癌症干细胞，但对于调节生理性造血的基因调控网络以及这些网络在白血病形成过程中是如何被破坏的，仍然没有明确的认识。我最感兴趣的是剖析这些造血网络的逻辑和性质，以及它们的构成因素如何受到外部条件的影响，例如利基信号，特别是缺氧。表征这种网络和/或外部条件的影响将有助于理解HSC的命运决定，这可能为HSC的体外扩增以及白血病发生的潜在机制提供洞察力，其标志是HSC命运决定的放松调控。理解和重建(或反之亦然)自然干细胞和/或组织是干细胞生物学和再生医学的组成部分。重建骨髓生态位可能会为体外扩增造血干细胞提供一个稳定的平台。从理论上讲，这样的合成系统应该提供了一个研究造血干细胞生物学的平台，一个可靠的方法来产生足够的HSC产量用于治疗性移植，以及一个体外药理筛选系统，可以为靶向LSC利基提供新的见解。由于骨髓的组织复杂性，以及合成形态学是一个非常年轻的领域，建立和理解更简单的系统是首要任务。为了实现这一点，我将热衷于：i)研究在形态发生模块的诱导中的已知基因，ii)将特定的模块链接和协调成特定的序列，以及iii)在这些模块和发育生物学的核心原理(例如图灵系统)之间建立联系。这种复杂的基因工程至少在理论上足以产生简单的图案化组织，但也将提供一个产生更复杂形态发生的平台。