ER stress and virulence of Aspergillus fumigatus

烟曲霉的内质网应激和毒力

基本信息

批准号：
7367672
负责人：
DAVID S ASKEW
金额：
$ 35.1万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7367672
关键词：
Antifungal Agents Antifungal Therapy Antineoplastic Agents Aspergillosis Aspergillus fumigatus Breathing Cell Nucleus Complex Condition Cytoplasm Data Degradation Pathway Disease Drug Delivery Systems Endopeptidases Endoplasmic Reticulum Endoplasmic Reticulum Degradation Pathway Environment Enzymes Epithelial Cells Eukaryota Eukaryotic Cell Exhibits Extracellular Protein Failure Future Gene Expression Genes Genetic Transcription Genome Grant Growth Homeostasis Human Immunocompromised Host Infection Invasive Life Style Lung Malignant Neoplasms Microarray Analysis Molds Molecular Molecular Chaperones Morbidity - disease rate Nutrient Nutritional Organ Transplantation Organism Orthologous Gene Outcome Pathogenesis Pathway interactions Peptide Hydrolases Phosphotransferases Polyribosomes Population Predisposition Prevalence Process Production Property Proteins Protozoa RNA Binding Reproduction spores Resistance Risk Role Secretory Cell Signal Pathway Stress System Testing Therapeutic Tissues Translations Ubiquitin Ubiquitin-Protein Ligase Complexes Virulence Work biological adaptation to stress cancer therapy clinical efficacy defined contribution design fungus gain of function in vivo insight loss of function mortality mouse model multicatalytic endopeptidase complex mutant novel pathogen prevent protein folding rapid growth response sensor synergism therapeutic target transcription factor ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Aspergillus fumigatus is an important opportunistic fungal pathogen that has become the leading infectious mould of immunocompromised patients. Despite some advances in therapy, invasive aspergillosis continues to have a poor outcome, emphasizing the need for more information on fungal pathways that are essential to the growth of the organism in vivo. A. fumigatus secretes tremendous quantities of extracellular proteins as part of its normal saprophytic lifestyle, which places it at high risk for protein unfolding and endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) counters this stress by upregulating the expression of genes involved in protein folding, secretion and degradation. In this grant, we provide preliminary data that A. fumigatus relies heavily upon the UPR to support the secretory activity that it needs to survive ER stress and acquire nutrients from host tissue. Secondly, we demonstrate that loss of UPR function exhibits potent synergism with existing antifungal drugs against A. fumigatus. Using mutants of the UPR and the related ER- associated degradation pathway (ERAD), we propose to validate ER stress responses as a therapeutic target for aspergillosis, and to gain insight into the key components of the response. The following specific Aims are proposed: Aim I will test the hypothesis that the UPR is essential for the growth of A. fumigatus under conditions of ER stress, and that it contributes to the ability of the organism to cause disease in vivo. Aim II will test the hypothesis that ERAD is also required to sustain growth under conditions of ER stress, and that it works in concert with the UPR to support the virulence of the organism in vivo. Aim III will use a genome-wide approach to identify novel components of the A. fumigatus ER stress response by testing the hypothesis that the response of A. fumigatus to ER stress involves specific changes in the transcription and translation of a subset of mRNAs. These studies have the potential to identify novel targets for the treatment of aspergillosis, and have broader implications for increasing the antifungal susceptibility profile of fungal species that are intrinsically resistant to existing antifungals.

描述（由申请人提供）：曲曲霉是一种重要的机会性真菌病原体，已成为免疫功能低下患者的主要感染模具。尽管在治疗方面取得了一些进步，但侵入性曲霉病仍会取得较差的结果，强调需要更多有关对体内生物生长至关重要的真菌途径的信息。 A. fumigatus分泌大量的细胞外蛋白，这是其正常的腐生生活方式的一部分，它使其具有蛋白质展开和内质网（ER）胁迫的高风险。展开的蛋白质反应（UPR）通过上调涉及蛋白质折叠，分泌和降解的基因的表达来抵消这种应激。在这笔赠款中，我们提供了烟曲霉的初步数据，严重依赖UPR来支持其生存的分泌活性，以使ER应力生存并从宿主组织中获取营养。其次，我们证明了UPR功能的丧失与现有的抗真菌药物相对于烟曲霉表现出有效的协同作用。使用UPR的突变体和相关的降解途径（ERAD），我们建议验证ER应力反应作为曲霉病的治疗靶标，并深入了解反应的关键成分。提出了以下具体目的：目标我将检验以下假设：在ER应激条件下，UPR对于烟曲霉的生长至关重要，并且它有助于生物体在体内引起疾病的能力。 AIM II将检验以下假设：在ER压力条件下还需要Erad来维持增长，并且它与UPR协同工作以支持体内生物体的毒力。 AIM III将使用全基因组的方法来鉴定烟曲霉的应激响应的新成分，即通过检验以下假设：烟曲霉对ER应激的响应涉及mRNA子集的转录和翻译的特定变化。这些研究有可能识别用于治疗曲霉病的新靶标，并且对增加对现有抗真菌性物质抗性的真菌物种的抗真菌易感性概况具有更大的影响。