Predictive Multiscale Modeling of Microbial Consortia Biofilms

描述（由申请人提供）：生物膜在医学、环境和工程微生物系统中普遍存在。大多数天然存在的微生物以混合物种生物膜的形式生长。这些复杂的生物膜聚生体由大量具有复杂相互作用的细胞表型组成，并自组织成三维结构。虽然是地球上绝大多数微生物生命的基础，但对聚生体生物膜的基本设计原理仍然知之甚少。我们认为，需要结合计算和实验工具来解决表征，预测和治疗这些复杂系统的挑战。该项目的总体目标是开发一个实验驱动的，预测多尺度模型，产生定量准确的预测生物膜形成动态，物种分布和扰动的反应。生物膜模型将通过将单个物种的基因组规模的代谢重建与营养物、代谢副产物和抗生素通过生物膜运输的反应扩散方程相结合来制定。生物膜模型将是多尺度的， 时间和长度尺度，与代谢模型连接个别基因的细胞动力学和财团模型连接个别细胞的社区动态。该研究将使用医学相关的三种慢性伤口模型系统进行开发。美国每年治疗慢性伤口的费用超过250亿美元，并且由于糖尿病和肥胖症的增加，预计费用将迅速增长。本研究的具体目标是：（1）构建和评估多物种聚生体生物膜的多尺度动态空间分辨代谢模型框架;（2）开发和实施空间分辨生物膜分析方法，以量化聚生体和单培养生物膜的生理学，为计算模型提供信息和验证;和（3）预测和测试对培养扰动的空间分辨代谢响应，包括用假设细化的迭代循环的抗生素处理。该研究的预期成果是：（1）用于微生物生物膜多尺度建模的一般方法和相关软件工具，以预测适合分布到多尺度建模社区的异质环境中的聚生体动态;（2）用于相互作用的聚生体生物膜内的质量和能量平衡的空间分辨测量的实验工具;（3）第一扰动分析 单一培养物和多物种慢性伤口生物膜对营养变化和抗生素治疗的影响;以及（4）提出了有效治疗微生物聚生体生物膜的治疗策略。

DESCRIPTION (provided by applicant): Biofilms are ubiquitous in medical, environmental, and engineered microbial systems. The majority of naturally occurring microbes grow as mixed species biofilms. These complicated biofilm consortia are comprised of a large number of cell phenotypes with complex interactions and self-organize into three-dimensional structures. While foundational to the vast majority of microbial life on the planet, the basic design principles of consortia biofilms are still poorly understood. We believe that a combination of computational and experimental tools is needed to address the challenge of characterizing, predicting and treating these complex systems. The overarching goal of this project is to develop an experimentally driven, predictive multiscale model that generates quantitatively accurate predictions of biofilm formation dynamics, species distributions and responses to perturbations. The biofilm model will be formulated by combining genome-scale metabolic reconstructions of individual species with reaction-diffusion equations for nutrient, metabolic byproduct and antibiotic transport through the biofilm. The biofilm model will be multiscale with respect to both time and length scales, with the metabolic models linking individual genes to cellular dynamics and the consortia model linking individual cells to community dynamics. The research will be developed using a medically relevant, three species chronic wound model system. Treatment of chronic wounds costs the US in excess of $25 billion per year and the costs are anticipated to grow rapidly due to the rise in diabetes and obesity. The specific aims of the proposed research are: (1) construct and evaluate a multiscale metabolic modeling framework for multispecies consortia biofilms in a dynamic, spatially resolved format; (2) develop and implement spatially resolved biofilm analytical methods to quantify physiologies of consortia and monoculture biofilms to inform and validate the computational model; and (3) predict and test spatially resolved metabolic responses to culturing perturbations including antibiotic treatments with iterative loops of hypothesis refinement. Expected outcomes of the proposed research are: (1) a general methodology and associated software tools for multiscale modeling of microbial biofilms to predict consortia dynamics in heterogeneous environments suitable for distribution to the multiscale modeling community; (2) experimental tools for spatially-resolved measurement of mass and energy balances within interacting consortia biofilms; (3) the first perturbation analysis of monoculture and multispecies chronic wound biofilms to nutrient variations and antibiotic treatments; and (4) proposed therapeutic strategies for effectively treating microbial consortia biofilms.