Looking into the Crystal Ball: Uncovering Predictive Mechanical Cues for Cell Choices in Development and Disease'

探究水晶球：揭示发育和疾病中细胞选择的预测机械线索

• 批准号: 2898814
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2898814
• 关键词: Looking; into; Crystal; Ball; Uncovering

The cells and tissues of our bodies are constantly pushed and pulled and it is vital that they sense and respond to these mechanical forces appropriately to maintain normal tissue function. This is particularly true during embryogenesis - the uniquely complex process of growing and shaping a whole organism from a single cell. We are beginning to understand some of the cellular mechanisms that link cell behaviour with mechanical force in isolated cells, but we know much less about how this applies to the complex tissues of our bodies. Bridging this gap is important since many common diseases, such as cancer, alter the mechanical properties of our tissues. In this project we will study how the physical environment of a tissue contributes to normal embryo development. Lessons learned from the embryo will then be applied to models of cancer development to reveal how cell and tissue responses to mechanical force are maintained or dysregulated during oncogenesis.We will use cutting-edge microscopy and mathematical modelling to unlock the complexity of mechano-regulation in "real-world" tissue environments. One fundamentally important, "real-world" tissue environment is the mammalian neural crest. Neural Crest Cells (NCCs) are a highly migratory and multipotent population of cells that play a major role in embryonic development. A crucial cell type derived from NCCs are melanocytes, which are pigment-producing cells in skin and the parent cell of melanoma, a devastating skin cancer. We will use a transgenic, fluorescent reporter mouse model (iDct-GFP) of embryonic melanocyte development. By applying a reproducible force to tissue explants under confocal imaging, we will map cell-shape changes in the mouse melanocyte precursor tissues when under known force regimes. We aim to explore the relationship between mechanical force and dynamic cell behaviours in the stretched tissue explants. This work will be taken forward in cutting-edge intravital imaging to observe the melanocytic lineage in a whole and living embryo and in mouse melanoma models of early tumour progression. This work will benefit from strong collaborations with the world-leading intravital expert, Dr Roberto Weigert (NCI, NIH, USA) and with the prestigious mouse melanoma model authority, Dr Glenn Merlino (NCI, NIH, USA). This project will include a potential visit to the NIH campus, USA, to further develop the technology/collaborations. This work has the potential to uncover a meaningful predictor for metastatic risk in early-stage melanoma tumours, which would revolutionise the way patient tumours are selected for further therapy. The project fits the BBSRC remit of "Advancing the frontiers of bioscience discovery" by addressing two priority areas:1. Understanding the rules of life: Our tissues exist in dynamic physical environments and their ability to sense and respond to mechanical force is vital for normal function. In this project we will determine how these physical "rules of life" regulate cell behaviour in complex tissue environments. We aim to reveal simple physical markers (e.g. cell geometry) that can predict future cell behaviour (e.g. proliferation, lineage commitment)2. Transformative technologies: We will use cutting edge in vivo/intravital imaging to track cell behaviour in complex tissues and combine this with mathematical modelling to infer mechanical stress. By mapping mechanical properties onto cell behaviours (and vice versa) we ultimately aim to build new tools to predict how individual cells will respond to their tissue microenvironment

我们体内的细胞和组织不断推动和拉动，至关重要的是，它们感知并适当地响应这些机械力以维持正常的组织功能。在胚胎发生过程中尤其如此 - 从单个细胞中生长和塑造整个生物的独特复杂过程。我们开始理解某些细胞机制，这些细胞机制将细胞行为与孤立细胞中的机械力联系起来，但是我们对这是如何应用于身体的复杂组织的了解较少。弥合此差距很重要，因为许多常见疾病（例如癌症）改变了我们组织的机械性能。在这个项目中，我们将研究组织的物理环境如何促进正常的胚胎发育。然后，从胚胎中学到的经验教训将应用于癌症发展模型，以揭示在肿瘤发生过程中如何保持细胞和组织对机械力的反应。我们将使用最先进的显微镜和数学建模来释放“现实世界”组织环境中机械调节的复杂性。从根本上重要的“现实世界”组织环境是哺乳动物神经rest。神经rest细胞（NCCS）是高度迁移和多核细胞种群，在胚胎发育中起主要作用。源自NCC的关键细胞类型是黑素细胞，它们是皮肤中产生色素的细胞和黑色素瘤的母细胞（一种毁灭性的皮肤癌）。我们将使用胚胎黑素细胞发育的转基因，荧光记者小鼠模型（IDCT-GFP）。通过在共焦成像下将可重复的力施加到组织外植体中，我们将在已知的力度状态下绘制小鼠黑素细胞前体组织中的细胞形变化。我们旨在探索拉伸组织外植体中机械力与动态细胞行为之间的关系。这项工作将在尖端的插入式成像中进行前进，以观察整体中的黑色素谱系，生存的胚胎以及早期肿瘤进展的小鼠黑色素瘤模型。这项工作将受益于与世界领先的插入专家Roberto Weigert博士（NCI，NIH，美国）以及享有声望的老鼠黑色素瘤模型管理局Glenn Merlino博士（NCI，NCI，NIH，美国）。该项目将包括潜在的访问美国NIH校园，以进一步开发技术/合作。这项工作有可能发现早期黑色素瘤肿瘤转移风险的有意义的预测因子，这将彻底改变患者肿瘤进行进一步治疗的方式。该项目符合BBSRC通过解决两个优先领域的BBSRC职位：1。了解生命的规则：我们的组织存在于动态的物理环境中，其感知和对机械力的感觉的能力对于正常功能至关重要。在这个项目中，我们将确定这些物理“生命规则”如何调节复杂组织环境中的细胞行为。我们旨在揭示可以预测未来细胞行为（例如增殖，谱系承诺）的简单物理标记（例如细胞几何形状）2。变革性技术：我们将使用体内/静脉内成像的尖端来跟踪复杂组织中的细胞行为，并将其与数学建模相结合以推断机械应力。通过将机械性能映射到细胞行为（反之亦然），我们最终旨在构建新工具，以预测单个细胞如何响应其组织微环境