Multiscale modeling of the battle over iron in invasive lung infection

侵袭性肺部感染中铁之争的多尺度建模

• 批准号: 10213617
• 负责人: REINHARD LAUBENBACHER
• 金额: $ 74.83万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-08 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213617
• 关键词: 3-Dimensional; Address; Animal Model; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Biological; Cells; Cessation of life; Communities; Complex; Data; Development; Disease; Environment; Epithelial; Event; Feedback; Goals; Health; Heme; Heme Iron; Hemorrhage; Homeostasis; Hormones; Host Defense; Human; Hybrids; Immune response; Immunity; Immunocompromised Host; Immunology; Impairment; In Vitro; Individual; Infection; Inhalation; Innate Immune Response; Intervention; Iron; Laboratories; Lead; Leukocytes; Life; Liver; Lung; Lung infections; Malignant Neoplasms; Mathematics; Modeling; Molecular; Mycoses; Organ; Organism; Outcome; Pharmaceutical Preparations; Population; Process; Production; Reproducibility; Reproduction spores; Research Personnel; Resistance; Resources; Respiratory Tract Infections; Role; Scientist; Signal Transduction; Software Design; System; Technology; Therapeutic; Therapeutic immunosuppression; Time; Tissues; Transplantation; antimicrobial; cell type; computerized tools; experimental study; flexibility; fungus; improved; in silico; in vivo; innovation; iron metabolism; mathematical model; microorganism; molecular modeling; molecular scale; monocyte; mouse model; multi-scale modeling; network models; neutrophil; novel; novel therapeutics; open source; pathogen; response; simulation; therapeutic target; tool; trend

PROJECT SUMMARY Invasive aspergillosis is among the most common fungal infection in immunocompromised hosts and carries a poor outcome. 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 against this infection, possibly in combination with antifungal drugs. Iron is essential to all living organisms, and restricting iron availability is a critical mechanism of antimicrobial host defense against many microorganisms; conversely, successful pathogens have evolved potent mechanisms for scavenging iron from the host. These mechanisms have the potential to be harnessed therapeutically, for example with drugs that enhance the host’s iron sequestration mechanisms. The overarching goal of this project is to develop a multi-scale mathematical model that can serve as a simulation tool of the role of iron in invasive aspergillosis. The model will integrate mechanisms at the molecular scale with tissue-level events and a whole-body scale capturing the role of the liver. The project brings an innovative approach to the study of this infection, and introduces innovative features to multiscale modeling through a novel modular software design that improves flexibility, reproducibility, and model sharing.

项目概要 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，并携带 致病微生物烟曲霉的孢子广泛分布于体内。 健康的宿主可以清除吸入的孢子而不会患病，但受损的个体则可以。 免疫力很容易受到危及生命的呼吸道感染的影响，然后传播到其他器官。 免疫抑制疗法在移植和癌症中的使用越来越多，显着增加 这种感染导致患者遭受痛苦和死亡，并且这种趋势预计将持续下去。 主要关注病原体，但更好地了解宿主防御的组成部分 这种感染可能会导致针对这种感染的新疗法的开发，可能是联合疗法 与抗真菌药物。 铁对于所有生物体都是必不可少的，限制铁的可用性是一个关键机制 相反，成功的病原体已经进化出针对许多微生物的抗菌宿主防御； 从宿主中清除铁的有效机制这些机制有可能被利用。 治疗上，例如使用增强宿主铁螯合机制的药物。 该项目的总体目标是开发一个可以作为模拟的多尺度数学模型 该模型将在分子尺度上整合铁的作用机制。 通过组织水平事件和全身尺度来捕捉肝脏的作用，该项目带来了创新。 研究这种感染的方法，并通过 新颖的模块化软件设计，提高了灵活性、可重复性和模型共享。