The systems biology of iron homeostasis and the immune response to Aspergillus

铁稳态的系统生物学和对曲霉菌的免疫反应

• 批准号: 8359974
• 负责人: REINHARD LAUBENBACHER
• 金额: $ 19.26万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359974
• 关键词: AIDS/HIV problem; Allergens; Allogenic; Alveolar Macrophages; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Asthma; Autologous; Bioinformatics; Biology; Breast; Cell Culture System; Cell Culture Techniques; Cessation of life; Clinic; Collaborations; Communicable Diseases; Complex; Computational Biology; Computer Simulation; Data; Disease; Enrollment; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Epithelium; Epstein-Barr Virus Infections; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Feedback; Gastrointestinal Diseases; Generations; Goals; Grant; Growth; Homeostasis; Human; Immune; Immune response; Immunocompromised Host; Immunology; Immunosuppression; In Vitro; Incidence; Infection; Infectious Disease Immunology; Inflammatory Response; Institutes; Iron; Laboratories; Lead; Letters; Lung; Malignant Neoplasms; Mammals; Mathematics; Measurement; Mediating; Medical Technology; Messenger RNA; Microbiology; Modeling; Molds; Montana; Mus; National Cancer Institute; National Institute of Allergy and Infectious Disease; Natural Immunity; Organ Transplantation; Outcome; Pathogenesis; Pathway interactions; Patients; Production; Proteins; Recording of previous events; Regulation; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Rheumatoid Arthritis; Risk; Role; Siderophores; Stem cell transplant; System; Systems Biology; Techniques; Time; Training; Transplant Recipients; Universities; Virginia; Virulence; Western Blotting; allergic airway disease; cell type; chemotherapy; computational network modeling; cytokine; design; experience; fungus; interest; iron metabolism; macrophage; mathematical model; meetings; member; mortality; novel therapeutics; pathogen; patient population; professor; programs; research study; resistant strain; response; therapeutic target; tool; working group

DESCRIPTION (provided by applicant): The specific aims of this project are designed to better understand the biology and virulence of Aspergillus fumigatus, the causative agent of invasive aspergillosis (IA), the host immune response, and the role of iron in the interaction between fungus and host. IA is an understudied disease of growing significance worldwide that causes over 3,500 annual deaths in the U.S. alone. The significance of IA is growing due to substantial increases in the number of allogenic and autologous stem cell transplants, as well as advances in medical technologies that are expanding the spectrum of patients susceptible to A. fumigatus infections. For example, while transplant patients remain the patient population most at risk, immunosuppression therapies are now routinely used to treat more common diseases including, asthma, rheumatoid arthritis, and gastrointestinal disorders. With the rising number of immunocompromised patients, the significance of invasive infections caused by A. fumigatus and other invasive moulds will undoubtedly continue to increase. In order to identify new and promising therapeutic targets to treat infection with this ubiquitous fungus, researchers have incorporated a systems biology approach to understand the fungal pathways contributing to virulence. The project proposed here applies this approach to the host response, a step toward the ultimate goal of integrating host and fungal pathways. While the host response is multi-pronged, a central factor in the interplay between the host and A. fumigatus is the manipulation of iron levels in both macrophages and epithelial cells. Iron homeostasis is regulated by a control system of proteins that are connected through several intertwined feedback loops. This complicates an understanding of the mechanisms that mediate the effect of cytokine production on iron levels. The focus of the proposed project is to elucidate the network of immune proteins and key proteins involved in iron homeostasis in both alveolar macrophages and lung epithelial cells, with the goal of identifying key drivers of iron regulation during Aspergillus infection. Th central discovery tool in the project will be a dynamic mathematical model of the network to be constructed that encodes the dynamic response and the effect of feedback loops under perturbations of key proteins. PUBLIC HEALTH RELEVANCE: This project is designed to better understand the biology and virulence of Aspergillus fumigatus, the causative agent of invasive aspergillosis (IA), the host immune response, and the role of iron in the interaction between fungus and host. It impacts our ability to identify novel therapeutic treatments for this understudied disease.

描述（由申请人提供）：该项目的具体目标旨在更好地了解烟曲霉（侵袭性曲霉病（IA）的病原体）的生物学和毒力、宿主免疫反应以及铁在两者之间相互作用中的作用。真菌和宿主。 IA 是一种尚未得到充分研究的疾病，其重要性在全球范围内日益凸显，仅在美国每年就会导致 3,500 多人死亡。由于同种异体和自体干细胞移植数量的大幅增加，以及医疗技术的进步扩大了易受烟曲霉感染的患者范围，IA 的重要性日益增强。例如，虽然移植患者仍然是风险最大的患者群体，但免疫抑制疗法现在通常用于治疗更常见的疾病，包括哮喘、类风湿性关节炎和胃肠道疾病。随着免疫功能低下患者数量的不断增加，烟曲霉和其他侵入性霉菌引起的侵入性感染的重要性无疑将继续增加。为了确定新的、有希望的治疗靶点来治疗这种普遍存在的真菌感染，研究人员采用了系统生物学方法来了解导致毒力的真菌途径。这里提出的项目将这种方法应用于宿主反应，朝着整合宿主和真菌途径的最终目标迈出了一步。虽然宿主反应是多方面的，但宿主和烟曲霉之间相互作用的一个核心因素是巨噬细胞和上皮细胞中铁水平的操纵。铁稳态由蛋白质控制系统调节，该控制系统通过几个相互交织的反馈回路连接。这使得对介导细胞因子产生对铁水平影响的机制的理解变得复杂。该项目的重点是阐明肺泡巨噬细胞和肺上皮细胞中参与铁稳态的免疫蛋白和关键蛋白网络，目的是确定曲霉感染期间铁调节的关键驱动因素。该项目的核心发现工具将是要构建的网络的动态数学模型，该模型对关键蛋白质扰动下的动态响应和反馈环路的影响进行编码。 公共健康相关性：该项目旨在更好地了解烟曲霉（侵袭性曲霉病 (IA) 的病原体）的生物学和毒力、宿主免疫反应以及铁在真菌和宿主相互作用中的作用。它影响了我们为这种尚未研究的疾病确定新疗法的能力。