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Aspergillus fumigatus infection and fibrosis

烟曲霉感染和纤维化

基本信息

批准号：
10367232
负责人：
DAVID S ASKEW
金额：
$ 40.5万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367232
关键词：
Ablation Acute Adult Respiratory Distress Syndrome Affect Allergic Bronchopulmonary Aspergillosis Aspergillosis Aspergillus Aspergillus fumigatus Atmosphere Behavior Biological Models Blood capillaries COVID-19 Cell Differentiation process Chronic Complication Connective Tissue Data Dendritic Cells Development Effectiveness Environment Enzymes Epithelial Exposure to Extracellular Matrix Failure Fibroblasts Fibrosis Foundations Fright Gene Expression Profile Genetic Genetic Models Genetic Transcription Geography Germination Goals Grant Growth Factor Hematogenous Hematopoietic stem cells Host Defense Host Defense Mechanism Human Hyphae Immune Immune system Immunocompetent Immunosuppression Incidence Individual Infection Inflammatory Inflammatory Response Inhalation Innate Immune System Knowledge Life Light Lung Lung infections Mediator of activation protein Molds Mus Myelogenous Myeloid Cells Opportunistic Infections Organ Transplantation Outcome Outcome Study Pathogenesis Pathogenicity Pathology Patients Pneumonia Population Process Production Pulmonary Fibrosis Pulmonary vessels Reproduction spores Severities Solid Structural defect Structure Structure of parenchyma of lung Testing Tissues Transplantation cell type cytokine fungus immunological status immunosuppressed improved outcome in vivo interstitial lung injury macrophage mouse genetics mouse model novel novel therapeutic intervention pathogen pathogenic fungus pathogenic microbe repaired respiratory respiratory pathogen response response to injury treatment strategy

项目摘要

Aspergillus fumigatus is an environmental mold that is responsible for a life-threatening pneumonia known as invasive aspergillosis. The infection begins with the inhalation of conidia (spores) into the lung. In a healthy individual, the spores are cleared by the immune system. However, in the immunosuppressed population, or patients in the ICU, failure to eradicate the fungus allows the spores to germinate. A. fumigatus releases an armamentarium of degradative enzymes as it grows, resulting in severe damage to the lung parenchyma. Fibroblasts are one of the major cell types that respond to tissue damage. In response to injury, these cells differentiate into an activated state, which is required to stabilize the tissue and promote repair. However, fibroblast activity is not restricted to matrix secretion; emerging evidence suggests that they also possess the ability to detect microbial pathogens and to respond by secreting mediators with the potential to contribute to pathogen clearance. In this grant, we propose to take advantage of unique genetic mouse models that we have developed to determine the contribution of pulmonary fibroblasts to the outcome of A. fumigatus exposure. We hypothesize that fibroblast activation in response to A. fumigatus-induced lung damage amplifies a protective inflammatory response. The proposed aims will test this hypothesis by determining the dynamics of fibroblast activation and deactivation in response to A. fumigatus in both immunocompetent and immunosuppressed mice, the transcriptional response of fibroblasts to A. fumigatus exposure, and the contribution of fibroblasts to pathogenic outcome in a mouse model of fibroblast ablation. The findings of this study will provide new information on mechanisms of host defense against A. fumigatus and potentially other pathogens that damage the human lung. 1

烟曲霉菌是一种环境霉菌，可导致危及生命的肺炎也就是侵袭性曲霉病感染开始于分生孢子（孢子）吸入肺部。中健康的个体，孢子被免疫系统清除。然而，在免疫抑制的在人群或ICU中的患者中，未能根除真菌会使孢子发芽。A.烟曲霉在生长过程中会释放大量的降解酶，导致肺部严重损伤薄壁组织成纤维细胞是响应组织损伤的主要细胞类型之一。为了应对伤害，这些细胞分化成活化状态，这是稳定组织和促进修复所必需的。然而，成纤维细胞的活性并不局限于基质分泌;新出现的证据表明，它们也具有检测微生物病原体的能力，并通过分泌具有潜在有助于病原体清除。在这项资助中，我们建议利用独特的遗传小鼠模型，我们已经开发了一种方法来确定肺成纤维细胞对A.烟曲霉 exposure.我们假设成纤维细胞对A.烟熏引起的肺损伤放大一种保护性炎症反应所提出的目标将通过确定成纤维细胞活化和失活响应于A.在免疫活性和免疫抑制小鼠，成纤维细胞对A.烟曲霉菌暴露，在成纤维细胞消融的小鼠模型中，成纤维细胞对致病结果的贡献。这项研究的结果研究结果为进一步了解A.烟曲霉菌和潜在的其他这些病原体会损害人的肺部。 1