Multiscale nuclear mechanobiology within the skin: from biophysical cues to epigenetic effects

皮肤内的多尺度核力学生物学：从生物物理线索到表观遗传效应

• 批准号: BB/P006108/1
• 负责人: John Connelly
• 金额: $ 59.85万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FP006108%2F1
• 关键词: Multiscale; nuclear; mechanobiology; within; skin

The epidermis of the skin forms an essential physical barrier to the external environment, and it is continuously exposed to complex biomechanical forces. While it is well known that mechanical and biophysical cues regulate diverse cellular functions, such as growth, migration, and survival, the molecular level mechanisms by which cells within the skin sense these forces remains poorly understood. As the nucleus is the central organelle within which DNA is packaged and this internal structure defines specific patterns of gene expression, we hypothesise that the nucleus is a major mechano-sensing element within the cell: Mechanically induced changes in nuclear shape influence the internal structure and transcription of genes. Indeed, our preliminary data indicate that keratinocytes exposed to defined physical cues display changes in nuclear size and shape, and these changes in nuclear morphology correlate with altered DNA structure.The overall objective of the proposed project is to understand how forces are transmitted from the external environment to the nucleus and to determine the subsequent effects on nuclear structure, gene expression, and cell function within the epidermis of the skin. We will use advanced biophysical and imaging techniques to apply forces to single cells, and systems biology methodologies to analyse the changes in DNA structure and gene expression. In addition, we will test the role of internal cellular structures, such as the cytoskeleton, to gain mechanistic insight into these processes. Finally, we will investigate the influence of nuclear mechano-sensing in more complex 3D models of human skin.The successful completion of this project will provide fundamental and significant insights into how cells sense mechanical forces, in particular the role of the nucleus. This knowledge will advance our understanding of normal skin physiology and mechanical function. Additional impacts of the proposed project include the development of new biophysical tools and technologies, building new collaborations with academics and industry, and multi-disciplinary training for the scientists involved. Future studies following on from this work could involve investigation of additional aspects of nuclear structure and examining the role of these mechanotransduction pathways in skin diseases such as blistering, scarring, or cancer.

皮肤的表皮形成对外部环境的基本物理屏障，并且其持续暴露于复杂的生物力学力。虽然众所周知，机械和生物物理线索调节不同的细胞功能，如生长，迁移和存活，但皮肤内细胞感知这些力的分子水平机制仍然知之甚少。由于细胞核是包装DNA的中央细胞器，并且这种内部结构定义了基因表达的特定模式，因此我们假设细胞核是细胞内的主要机械传感元件：机械诱导的核形状变化影响基因的内部结构和转录。事实上，我们的初步数据表明，角质形成细胞暴露于定义的物理线索显示核大小和形状的变化，这些核形态的变化与DNA结构的改变相关。拟议项目的总体目标是了解力如何从外部环境传递到细胞核，并确定对细胞核结构，基因表达，以及皮肤表皮内的细胞功能。我们将使用先进的生物物理和成像技术对单细胞施加力，并使用系统生物学方法来分析DNA结构和基因表达的变化。此外，我们将测试内部细胞结构的作用，如细胞骨架，以获得对这些过程的机械见解。最后，我们将在更复杂的人体皮肤3D模型中研究核机械传感的影响。该项目的成功完成将为细胞如何感知机械力，特别是细胞核的作用提供基础和重要的见解。这些知识将促进我们对正常皮肤生理和机械功能的理解。拟议项目的其他影响包括开发新的生物物理工具和技术，与学术界和工业界建立新的合作关系，以及对有关科学家进行多学科培训。这项工作之后的未来研究可能涉及核结构的其他方面的调查，并检查这些机械转导通路在皮肤疾病，如起泡，疤痕或癌症中的作用。

项目成果

Actomyosin and vimentin cytoskeletal networks regulate nuclear shape, mechanics and chromatin organization.

肌动球蛋白和波形蛋白细胞骨架网络调节核形状、力学和染色质组织。

• DOI: 10.1038/s41598-017-05467-x
• 发表时间: 2017-07-12
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Keeling MC;Flores LR;Dodhy AH;Murray ER;Gavara N
• 通讯作者: Gavara N

Extracellular Adhesive Cues Physically Define Nucleolar Structure and Function.

• DOI: 10.1002/advs.202105545
• 发表时间: 2022-04
• 期刊: Advanced science (Weinheim, Baden-Wurttemberg, Germany)
• 作者: Pundel OJ;Blowes LM;Connelly JT
• 通讯作者: Connelly JT

High-Content Analysis of Cell Migration Dynamics within a Micropatterned Screening Platform.

微图案筛选平台内细胞迁移动力学的高内涵分析。

• DOI: 10.1002/adbi.201900011
• 发表时间: 2019
• 期刊: Advanced biosystems
• 影响因子: 4.1
• 作者: Almeida FV

The keratin network of intermediate filaments regulates keratinocyte rigidity sensing and nuclear mechanotransduction.

• DOI: 10.1126/sciadv.abd6187
• 发表时间: 2021-01
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Laly AC;Sliogeryte K;Pundel OJ;Ross R;Keeling MC;Avisetti D;Waseem A;Gavara N;Connelly JT
• 通讯作者: Connelly JT