Multiscale modeling of biological systems: An integrative approach

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。这项研究的主要目的是通过实验研究和定量方法相结合的方法来更基本地了解生物系统的复杂过程。**上皮-间充质转变(EMT)是一个生物学过程，在这个过程中，上皮细胞经历了多种生化变化，并具有间质特征，包括增强的迁移、侵袭能力和对凋亡的抵抗力。这一转变是胚胎发育、伤口愈合和转移的关键过程。此外，最近的研究将EMT与在正常细胞和肿瘤细胞群体中获得干细胞样特征联系起来。组织微环境因素，如低氧条件，也可能诱导细胞内EMT。低氧诱导的转换似乎伴随着Akt的激活和随后的下游信号转导。此外，线粒体在低氧时产生的活性氧增加，从而导致EMT的诱导。此外，肿瘤干细胞的表型受微环境因素缺氧和酸度的调节。**这项建议旨在应用一种综合的方法，对EMT、干细胞和组织微环境之间的联系进行三方面的研究。现有的实验数据将与现有的和新的数学模型相结合，研究低氧、酸度和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式到系统的数值模拟。本建议旨在研究(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在EMT中的作用，(3)EMT、SCs和其他相关途径之间的分子联系。

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.