Modular design of multiscale models, with an application to the innate immune response to fungal respiratory pathogens.

多尺度模型的模块化设计，应用于对真菌呼吸道病原体的先天免疫反应。

• 批准号: 9361210
• 负责人: REINHARD LAUBENBACHER
• 金额: $ 73.02万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9361210
• 关键词: Address; Animal Model; Architecture; Aspergillosis; Aspergillus; Aspergillus fumigatus; Biochemical; Biological; Biological Sciences; Biophysics; Breathing; Cells; Cessation of life; Communities; Complex; Computer Simulation; Computer software; Data; Data Set; Development; Disease; Docking; Environment; Goals; Health; Homeostasis; Hormones; Host Defense; Human; Imagery; Immune response; Immunity; Immunocompromised Host; Immunology; Impairment; In Vitro; Individual; Infection; Innate Immune Response; Intervention; Iron; Laboratories; Lead; Leukocytes; Life; Link; Liver; Lung; Malignant Neoplasms; Mathematics; Modeling; Molecular; Molecular Models; Mycoses; Organ; Organism; Outcome; Pharmaceutical Preparations; Population; Process; Production; Reproducibility; Reproduction spores; Research Personnel; Resources; Respiratory Tract Infections; Role; Running; Scientist; Signal Transduction; Software Design; Technology; Testing; Therapeutic; Therapeutic immunosuppression; Tissues; Transplantation; Validation; Whole Organism; animation; antimicrobial; cell type; data visualization; design; experimental study; fungus; in vivo; iron metabolism; light weight; mathematical model; monocyte; mortality; multi-scale modeling; network models; neutrophil; novel; novel strategies; open source; outcome forecast; pathogen; respiratory; response; simulation; statistics; technology development; tool; trend; usability; user-friendly; virtual

PROJECT SUMMARY Increased availability of biomedical data sets across spatial and temporal scales makes it possible to calibrate complex models that capture integrated processes from the molecular to the whole organism level. This complexity poses multiple challenges related to mathematical modeling, software design, validation, reproducibility, and extensibility. Visualization of model features and dynamics is a key factor in the usability of models by domain experts, such as experimental biologists and clinicians. The proposed project addresses these challenges in the context of the immune response to an important respiratory fungal infection. Its goal is to develop a novel modular approach to model architecture, using a recently introduced technology of lightweight virtual machines and our user-friendly open-source platform for the construction and linking of these so-called “Docker containers” to create complex modular models in a transparent fashion. A key benefit of software containers is that they can encompass the entire computational environment of a model, enabling unprecedented reproducibility of computational results. The overarching computational goal is to develop a novel approach to the modular design of multiscale models. While broadly applicable, this novel computational modeling approach will be focused on the development of a multiscale model capturing the early stages of invasive aspergillosis, an important health problem. Invasive aspergillosis is one of the most common fungal infections in immunocompromised hosts and carries a poor prognosis. The spores of the causative organism, Aspergillus fumigatus, are ubiquitously distributed in the environment. Healthy hosts clear the inhaled spores without developing disease, but individuals with impaired immunity are susceptible to a life-threatening respiratory infection that can then disseminate to other organs. The increasing use of immunosuppressive therapies in transplantation and cancer has dramatically increased suffering and death from this infection, and this trend is expected to continue. Current therapeutic approaches have been focused primarily on the pathogen, but a better understanding of the components of host defense in this infection may lead to the development of new treatments. In particular, restricting iron availability is a critical mechanism of antimicrobial host defense; conversely, successful pathogens have evolved potent mechanisms for scavenging iron from the host. These mechanisms have the potential to be harnessed therapeutically. The biological focus of the proposed project is the battle over iron between the fungus and the host. The overarching biomedical goal is to develop a simulation tool to explore the role of iron in invasive aspergillosis across biochemical and biophysical conditions.

项目概要 跨空间和时间尺度的生物医学数据集可用性的增加使得校准成为可能 捕捉从分子到整个生物体水平的综合过程的复杂模型。 复杂性带来了与数学建模、软件设计、验证相关的多重挑战 模型特征和动态的可视化是可用性的关键因素。 拟议的项目解决了领域专家（例如实验生物学家和信徒）的模型。 这些挑战是针对重要的呼吸道真菌感染的免疫反应的。 使用最近引入的技术开发一种新颖的模块化模型架构方法 轻量级虚拟机以及我们用于构建和链接这些虚拟机的用户友好的开源平台 所谓的“Docker 容器”以透明的方式创建复杂的模块化模型的一个关键好处。 软件容器的特点是它们可以包含模型的整个计算环境，从而使 计算结果的前所未有的可重复性总体计算目标是开发一个 多尺度模型模块化设计的新方法虽然广泛适用，但这种新颖的计算方法。 建模方法将侧重于开发捕捉早期阶段的多尺度模型 侵袭性曲霉病，一个重要的健康问题。 侵袭性曲霉病是免疫功能低下宿主中最常见的真菌感染之一， 致病微生物烟曲霉的孢子无处不在。 分布在环境中的健康宿主会清除吸入的孢子，但不会患病。 免疫力受损的人容易受到危及生命的呼吸道感染，然后 传播到其他器官。在移植和移植中越来越多地使用免疫抑制疗法。 癌症大大增加了这种感染造成的痛苦和死亡，预计这一趋势将 目前的治疗方法主要集中在病原体上，但有更好的方法。 了解这种感染中宿主防御的组成部分可能会导致新的开发 特别是，限制铁的利用率是抗菌宿主防御的关键机制； 相反，成功的病原体已经进化出从宿主中清除铁的有效机制。 该机制有可能被用于治疗。拟议项目的生物学重点是。 真菌和宿主之间的铁之战的总体生物医学目标是开发一种 模拟工具通过生物化学和生物物理探索铁在侵袭性曲霉病中的作用 状况。