Multiscale modeling of biological systems: An integrative approach

生物系统的多尺度建模：一种综合方法

• 批准号: RGPIN-2014-03615
• 负责人: Kohandel, Mohammad
• 金额: $ 2.99万
• 依托单位: University of Waterloo
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=565981
• 关键词: Multiscale; modeling; biological; systems; integrative

The application of mathematical and computational models to biology is an exciting and novel area of research in Applied Mathematics. The main objective of this research is to gain a more fundamental understanding of the complex processes of biological systems by integrating experimental studies and quantitative approaches. The epithelial-mesenchymal transition (EMT) is a biological process wherein epithelial cells undergo multiple biochemical changes and adopt mesenchymal features including an enhanced capacity for migration, invasiveness, and elevated resistance to apoptosis. This transition is a critical process during embryonic development, wound healing and metastasis. Further, recent studies have linked EMT with the acquisition of stem cell like characteristics in normal and neoplastic cell populations. Tissue microenvironmental factors, such as hypoxic conditions, may also induce EMT in cells. Hypoxia-induced transition seems to be accompanied by increased activation of Akt and subsequent downstream signaling. Moreover, mitochondrial production of reactive oxygen species is increased during hypoxia, resulting in the induction of EMT. In addition, the cancer stem cell phenotype is regulated by the microenvironmental factors hypoxia and acidity. This proposal aims to apply an integrative approach to provide a three-faceted study of the links between EMT, stem cells and tissue microenvironment. The available experimental data will be combined with existing and novel mathematical models to investigate the effects of hypoxia, acidity and EMT on properties of stem cells. These mathematical models range from deterministic and stochastic differential equations to numerical simulations of the system. This proposal aims to study (1) the effects of tissue microenvironmental factors on EMT and SCs, (2) the role of cell metabolism and antioxidants on EMT, and (3) the molecular links between EMT, SCs, and other related pathways.

数学和计算模型在生物学中的应用是应用数学中一个令人兴奋和新颖的研究领域。本研究的主要目的是通过结合实验研究和定量方法，对生物系统的复杂过程有更基本的了解。上皮-间充质转化（epithelial-mesenchymal transition， EMT）是上皮细胞经历多种生化变化并呈现间充质特征的生物学过程，包括迁移能力增强、侵袭性增强和对凋亡的抗性增强。这种转变是胚胎发育、伤口愈合和转移的关键过程。此外，最近的研究将EMT与正常和肿瘤细胞群体中干细胞样特征的获得联系起来。组织微环境因素，如缺氧条件，也可能诱导细胞发生EMT。缺氧诱导的过渡似乎伴随着Akt和随后的下游信号的激活增加。此外，缺氧时线粒体活性氧的产生增加，导致EMT的诱导。此外，肿瘤干细胞表型受缺氧和酸度等微环境因子的调控。本提案旨在应用综合方法，从三个方面研究EMT、干细胞和组织微环境之间的联系。实验数据将结合现有的和新的数学模型来研究缺氧、酸性和EMT对干细胞特性的影响。这些数学模型的范围从确定性和随机微分方程到系统的数值模拟。本课题旨在研究(1)组织微环境因素对EMT和SCs的影响；(2)细胞代谢和抗氧化剂对EMT的作用；(3)EMT与SCs及其他相关通路之间的分子联系。