Predictive Multiscale Modeling of Microbial Consortia Biofilms

描述(由申请人提供)：生物膜在医疗、环境和工程微生物系统中普遍存在。大多数自然产生的微生物以混合物种生物膜的形式生长。这些复杂的生物膜联合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。虽然生物膜是地球上绝大多数微生物生命的基础，但人们对生物膜的基本设计原则仍然知之甚少。我们认为，需要结合计算和实验工具来解决表征、预测和处理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、预测性的多尺度模型，该模型能够对生物膜形成动力学、物种分布和对扰动的反应产生定量准确的预测。生物膜模型将结合个体物种基因组规模的代谢重建和营养物质、代谢副产物和抗生素在生物膜中传输的反应-扩散方程来建立。生物膜模型将是关于两者的多尺度模型 时间和长度尺度，代谢模型将个体基因与细胞动力学联系起来，联合体模型将个体细胞与群落动力学联系起来。这项研究将使用与医学相关的三种慢性伤口模型系统进行。美国每年治疗慢性伤口的费用超过250亿美元，由于糖尿病和肥胖症的增加，预计费用将迅速增长。拟议研究的具体目标是：(1)以动态的、空间可分辨的形式构建和评估多物种联合生物膜的多尺度代谢建模框架；(2)开发和实施空间可分辨生物膜分析方法来量化联合生物膜和单一培养生物膜的生理，以告知和验证计算模型；以及(3)预测和测试对包括抗生素处理在内的培养扰动的空间分辨代谢响应，并通过迭代假设改进循环。拟议研究的预期结果是：(1)用于微生物生物膜多尺度建模的通用方法和相关软件工具，以预测适合于分布到多尺度建模社区的异质环境中的联合体动态；(2)用于相互作用的联合体内质量和能量平衡的空间分辨测量的实验工具；(3)第一次扰动分析 从单一培养和多物种慢性创面生物膜到营养变异和抗生素治疗；以及(4)提出了有效治疗微生物群落生物膜的治疗策略。

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.