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

今天可获得的丰富的生物医学数据--通常具有广泛的大小和时间尺度--允许验证和校准复杂的计算模型，这些模型集成了从分子到整个生物体的各个层面。为了使这些模型可供科学家和临床医生使用，他们是正在建模的生物医学现象的专家，重要的是要以可视的方式呈现模型的特征和活动，使它们易于理解。该项目寻求开发一种新颖的、模块化的计算方法来应对这一挑战。它将使用对一种重要的呼吸道真菌感染的免疫反应的建模作为试验台，以演示这种方法的可行性和有效性。这个项目将促进生物医学系统的计算建模和感染的病理生理学方面的知识。这种特殊的感染已变得越来越重要，因为它最常发生在免疫受损的人身上，包括癌症和移植患者。开发的模型将检查个人的免疫系统如何与真菌孢子相互作用，以更好地了解这种感染的进展。最终的目标将是利用这种改进的理解来刺激这种真菌感染的新治疗方法的开发。这种多尺度生物医学过程模型的复杂性带来了与数学建模、软件设计、验证、重复性和可扩展性相关的多重挑战。该项目的计算目标是开发一种新的模块化模型体系结构方法，使用最近引入的轻量级虚拟机技术和用户友好的开源平台来构建和链接这些所谓的“Docker Containers”，以透明的方式创建复杂的模块化模型。软件容器的一个关键好处是，它们可以涵盖模型的整个计算环境，从而实现前所未有的计算结果的重现性。对于这个项目，这个计算模型将专注于开发一个多尺度模型来捕捉侵袭性曲霉病的早期阶段。侵袭性曲霉病是免疫功能低下的宿主中最常见的真菌感染之一，预后不良。病原菌烟曲霉的孢子广泛分布于环境中。健康的宿主清除吸入的孢子不会发展成疾病，但免疫力受损的人容易受到威胁生命的呼吸道感染，然后可以传播到其他器官。在移植和癌症中越来越多地使用免疫抑制疗法，大大增加了这种感染造成的痛苦和死亡，预计这一趋势将继续下去。拟议项目的生物医学焦点是真菌和宿主之间的铁之争。生物医学的总体目标是开发一种模拟工具，以探索铁在生化和生物物理条件下侵袭性曲霉病中的作用。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The wealth of biomedical data available today -- often with wide ranging size and time scales -- allows for the validation and calibration of complex computational models that integrate across levels from molecules to whole organisms. For those models to be usable by scientists and clinicians who are experts in the biomedical phenomenon being modeled, it is important that the model features and activity be presented visually to make them understandable. This project seeks to develop a novel, modular computational approach to this challenge. It will use modeling of the immune response to an important respiratory fungal infection as a test bed to demonstrate the feasibility and effectiveness of this approach. This project will advance knowledge in computational modeling of biomedical systems and in the pathophysiology of infection. This particular infection has become increasingly relevant as it occurs most frequently in immuno-compromised individuals, including cancer and transplant patients. The developed model will examine how an individual's immune system interacts with the fungal spores to better understand the progression of this infection. The eventual goal would be to take advantage of this improved understanding to spur the development of new treatments for this fungal infection.This complexity of multiscale models of biomedical processes poses multiple challenges related to mathematical modeling, software design, validation, reproducibility, and extensibility. The computational goal of this project is to develop a novel modular approach to model architecture, using a recently introduced technology of lightweight virtual machines and a 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. For this project, this computational modeling will be focused on the development of a multiscale model capturing the early stages of invasive aspergillosis. 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. The biomedical 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.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.