Multiscale modelling of cellular oscillators: applications to vertebrate segmentation and hair follicle cycling.

细胞振荡器的多尺度建模：在脊椎动物分割和毛囊循环中的应用。

• 批准号: EP/F069200/1
• 负责人: Ruth Baker
• 金额: $ 31.97万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FF069200%2F1
• 关键词: Multiscale; modelling; cellular; oscillators; applications

The dramatic advances made in genetic and molecular biology in recent years have resulted in detailed descriptions of a number of complex processes that arise on many different spatial and temporal scales. This unparalleled flood of data may well enable us to understand how genes and proteins work collectively in a cell and from this how multi-cellular organisms develop. However, therein lies one of the great challenges of modern science: all too often our knowledge remains in isolated pockets, lacking a conceptual framework tying the fragmented data together and allowing ideas and hypotheses to be generated and tested. This is where mathematical modelling and numerical simulation can play a fundamental role, comparable with any research tool; they allow us to combine the effects of multiple non-linear processes into a coherent structure that can be used for the generation of hypotheses and experimentally testable predictions. In particular we will be interested in modelling two paradigm systems of biological oscillators: a molecular clock involved in segmentation of the head-tail axis of vertebrate embryos and the hair follicle cycle. Somitogenesis, segmentation of the head-tail axis of vertebrate embryos into repeated units known as somites, results in formation of precursors of the vertebrae, ribs and associated musculature. The somites consist of tightly bound blocks of cells, one of each side of the spinal chord, and they form in a strict spatio-temporal order: from head to tail, at well-defined time intervals. Before becoming incorporated into somites, cells lying along the head-tail axis exhibit oscillations in a number of gene products. These oscillations are synchronised via cell-cell signalling, resulting in travelling bands of gene expression that begin in the tail and are stabilised in the newly forming somites. Disruption of cell-cell signalling results in segmental defects that are characterised by malformed ribs and vertebrae.The skin of many mammals is covered with hair follicles, each undergoing regenerative cycling. The reasons for this cycling are plentiful: to allow for expansion and growth, to control hair length, to adapt to changing environmental and social conditions and to protect against the malignant degeneration associated with rapidly dividing tissue. Each hair follicle goes through a series of stages with the transformations between cycle stages dependent on secretion, by the follicles, of chemicals into the local environment. Many hair growth defects can be characterised by incorrect rates of progression through the follicular cycle and give rise to disorders such as alopecia. The main aim of this project is to develop novel mathematical and computational techniques in order to model the systems of oscillating biological elements described previously. We will assume each individual element can display either sustained or excitable oscillations (requires a supra-threshold stimulus in order to exhibit an oscillation) and that it interacts with other elements in the field. Depending on the level of interaction the system may display synchronised oscillations on a tissue level. However, this synchronisation can be disturbed by, for example, external influence from the environment or variation in the oscillation frequency of individual elements. Mathematical techniques will be developed and numerical simulations employed to describe the behaviour of the individual oscillators and different forms for their interaction. The models will be constructed using currently available biological hypotheses, parametrised and tested against experimental observations. In turn, the models will be used to generate hypotheses and experimentally testable predictions which will further our understanding in the area.

近年来，遗传和分子生物学取得了巨大进展，详细描述了许多不同时空尺度上出现的复杂过程。这一空前的数据洪流很可能使我们能够了解基因和蛋白质如何在细胞中共同工作，以及多细胞生物体如何发展。然而，现代科学面临的一个巨大挑战是：我们的知识往往仍然处于孤立的口袋中，缺乏一个概念框架，将支离破碎的数据联系在一起，并允许产生和测试想法和假设。这就是数学建模和数值模拟可以发挥基本作用的地方，可以与任何研究工具相媲美;它们使我们能够将多个非线性过程的影响联合收割机组合成一个连贯的结构，可以用于生成假设和实验可检验的预测。特别是，我们将有兴趣在建模两个范例系统的生物振荡器：一个分子时钟参与分割的头-尾轴的脊椎动物胚胎和毛囊周期。体节发生，脊椎动物胚胎的头-尾轴分裂成称为体节的重复单位，导致椎骨、肋骨和相关肌肉组织的前体形成。体节由紧密结合的细胞块组成，脊髓的每一侧都有一个，它们按照严格的时空顺序形成：从头到尾，以明确的时间间隔形成。在被整合到体节之前，位于沿着头尾轴的细胞在许多基因产物中表现出振荡。这些振荡通过细胞-细胞信号同步，导致基因表达的移动带，其开始于尾部，并在新形成的体节中稳定。细胞间信号传导的中断会导致以畸形的肋骨和椎骨为特征的节段性缺陷。许多哺乳动物的皮肤上覆盖着毛囊，每个毛囊都在经历再生循环。这种循环的原因很多：允许扩张和生长，控制头发长度，适应不断变化的环境和社会条件，并防止与快速分裂组织相关的恶性变性。每个毛囊都经历一系列的阶段，周期阶段之间的转换取决于毛囊分泌的化学物质进入局部环境。许多毛发生长缺陷的特征可以是通过毛囊周期的不正确的进展速率，并引起诸如脱发的疾病。该项目的主要目的是开发新的数学和计算技术，以模拟先前描述的振荡生物元件系统。我们将假设每个单独的元素可以显示持续或可激发的振荡（需要阈上刺激才能显示振荡），并且它与场中的其他元素相互作用。根据相互作用的水平，系统可以在组织水平上显示同步振荡。然而，这种同步可能受到例如来自环境的外部影响或各个元件的振荡频率的变化的干扰。数学技术将被开发和数值模拟来描述的行为的各个振荡器和不同形式的相互作用。这些模型将使用目前可用的生物学假设构建，并根据实验观察进行参数化和测试。反过来，这些模型将用于生成假设和实验可检验的预测，这将进一步加深我们对该领域的理解。

项目成果

Modelling hair follicle growth dynamics as an excitable medium.

• DOI: 10.1371/journal.pcbi.1002804
• 发表时间: 2012
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Murray PJ;Maini PK;Plikus MV;Chuong CM;Baker RE
• 通讯作者: Baker RE