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Multistationarity and Oscillations in Biochemical Reaction Networks

生化反应网络中的多重平稳性和振荡

基本信息

批准号：
1517577
负责人：
Casian Pantea
金额：
$ 19.8万
依托单位：
West Virginia University Research Corporation
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2019-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1517577&HistoricalAwards=false
关键词：
Multistationarity Oscillations Biochemical Reaction Networks

项目摘要

This project focuses on two of the most important behaviors in biological dynamics, playing key roles at all scales, from molecular to cellular, to tissues and organisms. Multistationarity refers to the capacity of a system to operate at alternative steady-states, and is observed experimentally as irreversible switch-like behavior; oscillatons are periodic variations in the concentration of interacting elements (genes, metabolites, enzymes, etc). The interplay of multistationary and oscillatory behavior underlies crucial physiological processes: cellular division, differentiation and apoptosis, cellular signaling, enzyme regulation, circadian rhythms, and membrane potential activity in neurons and heart cells are only a few examples. Many diseases involve disturbances of these processes as a result of deregulation of multistationary and oscillatory behaviors in specific gene networks or biological pathways. A better understanding of the two behaviors may lead to developments in the study of such diseases. In this project, the investigator will create mathematical tools and software that will allow biochemical and biomedical scientists to analyze dynamical features of relevant biological systems. The emergence of multistationarity and oscillation is intimately linked to the existence of feedbacks and to other subtle features of the structure (i.e. wiring diagram) in the underlying reaction network of interacting elements. Design principles associated to multistationarity and oscillations have long been proposed and refined over the years, but there is not yet a complete picture of the relationship between structure on one hand and multistationary or oscillatory behavior on the other. In this project, the investigator develops new mathematical theory and expand existing results to strengthen our understanding of this connection. In particular, algorithms will be developed to identify key structural properties of biochemical reaction networks that give rise to multistationarity and oscillation. These developments will be implemented in user friendly, open source software, to assist and complement theoretical and experimental work in biochemical and biomedical fields. For example, in a joint effort with experimental collaborators, the investigator will analyze the ERBB network of receptor tyrosine kinases whose multistable behavior is involved in early events in cancer onset. This work also opens up exciting possibilities in bioengineering for the design of reaction networks with prescribed properties, relevant to research in cellular differentiation and with applications to tissue engineering and drug development.

该项目关注生物动力学中最重要的两种行为，从分子到细胞，再到组织和有机体，在所有尺度上都发挥着关键作用。多稳态是指系统在交替的稳态下运行的能力，在实验上被观察到是不可逆的开关行为；振荡是相互作用元素(基因、代谢产物、酶等)浓度的周期性变化。多稳态和振荡行为的相互作用是重要的生理过程的基础：细胞分裂、分化和凋亡、细胞信号、酶调节、昼夜节律和神经元和心脏细胞的膜电位活动只是其中的几个例子。许多疾病涉及这些过程的干扰，这是由于特定基因网络或生物途径中的多稳态和振荡行为的放松管制造成的。对这两种行为的更好理解可能会导致此类疾病研究的发展。在这个项目中，研究人员将创建数学工具和软件，使生化和生物医学科学家能够分析相关生物系统的动力学特征。多平稳性和振荡的出现与反馈的存在和相互作用元素的基本反应网络中结构的其他微妙特征(即接线图)密切相关。多年来，与多平稳和振荡相关的设计原则早已被提出和完善，但对于结构与多平稳或振荡行为之间的关系，目前还没有一个完整的图景。在这个项目中，研究人员开发了新的数学理论，并扩展了现有的结果，以加强我们对这种联系的理解。特别是，将开发算法来识别导致多平稳和振荡的生化反应网络的关键结构属性。这些开发将在用户友好的开源软件中实施，以协助和补充生化和生物医学领域的理论和实验工作。例如，在与实验合作者的共同努力下，研究人员将分析受体酪氨酸激酶的ERBB网络，其多稳定行为与癌症发病的早期事件有关。这项工作还为生物工程中设计具有特定性质的反应网络开辟了令人兴奋的可能性，与细胞分化研究以及组织工程和药物开发的应用相关。