Translational repression & Aspergillus fumigatus virulence

转化抑制

基本信息

批准号：
8681609
负责人：
DAVID S ASKEW
金额：
$ 22.31万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8681609
关键词：
Antifungal Agents Antifungal Therapy Aspergillus fumigatus Characteristics Data Development Disease Endoplasmic Reticulum Environment Eukaryotic Initiation Factors Fractionation Future Generations Genes Genome Hematologic Neoplasms Homeostasis Homologous Gene In Vitro Infection Lead Life Lung Mammals Mediating Messenger RNA Molds Mutation Nature Organ Transplantation Organelles Organism Outcome Outcome Study Pathogenicity Pathway interactions Patients Phosphorylation Phosphotransferases Physiology Polyribosomes Predisposition Prokaryotic Initiation Factor-2 Protein Biosynthesis Proteins Reliance Repression Resistance Serine Signal Pathway Signal Transduction Stress Testing Therapeutic Translational Repression Translations Virulence Work Workload biological adaptation to stress cell type combat endoplasmic reticulum stress fungus insight mortality mutant novel novel strategies outcome forecast pathogen prevent protein folding public health relevance response restoration sensor trait transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Infections with the opportunistic mold Aspergillus fumigatus continue to be a major threat to the management of patients with hematologic malignancies and organ transplants. Since current antifungal therapies are unable to prevent a high rate of mortality for this disease, there is a need for more information on fungal pathways that allow this organism to thrive in the host environment. Recent studies have shown that A. fumigatus, and other pathogenic fungi, rely heavily on the unfolded protein response (UPR) for infection. The UPR is an adaptive response to endoplasmic reticulum (ER) stress, responsible for adjusting the protein folding capacity of the ER in proportion to the demand placed on the secretory pathway. In mammals, an important branch of the UPR is translational repression mediated by eIF2¿ phosphorylation, a pathway that lowers the influx of nascent proteins into the ER when the organelle is overloaded. Our preliminary data demonstrate that an analogous pathway is present in A. fumigatus, which challenges the existing paradigm of fungal UPR signaling. The overarching hypothesis to be tested in this proposal is that translational repression is a vital stress response of A. fumigatus that contributes to the virulence and antifungal drug susceptibility of this organism. The first aim will use mutants of the pathway to determine the impact of eIF2¿ phosphorylation and translational repression on the ability of the fungus to cause infection and to withstand antifungal drugs and other types of stress. Secondly, an important characteristic of the mammalian pathway is that a limited subset of mRNAs with key functions in ER homeostasis can escape translational repression. Thus, a second aim will use RNA-seq and polysome fractionation to identify mRNAs that show increased translation during ER stress. The outcome of this study is expected to uncover a new paradigm for the fungal ER stress response, which could lead to the development of novel strategies to combat infections with A. fumigatus, and potentially other eukaryotic pathogens that exploit the UPR for virulence.

描述（由申请人提供）：机会性霉菌烟曲霉感染仍然是血液恶性肿瘤和器官移植患者治疗的主要威胁，因为目前的抗真菌疗法无法预防这种疾病的高死亡率。需要更多关于使这种生物体在宿主环境中繁衍生息的真菌途径的信息，最近的研究表明，烟曲霉和其他病原真菌严重依赖于真菌。感染的未折叠蛋白反应（UPR）是对内质网（ER）应激的适应性反应，负责根据分泌途径的需求调整内质网的蛋白质折叠能力，这是哺乳动物的一个重要分支。 UPR 的翻译抑制是由 eIF2 介导的我们的初步数据表明，烟曲霉中也存在类似的途径，这挑战了真菌 UPR 信号传导的现有范式。该提案测试的是，翻译抑制是烟曲霉的重要应激反应，有助于该生物体的毒力和抗真菌药物敏感性。将使用该途径的突变体来确定 eIF2 的影响¿其次，哺乳动物途径的一个重要特征是，在内质网稳态中具有关键功能的有限 mRNA 子集可以逃避翻译抑制。因此，第二个目标是使用 RNA-seq 和多核糖体分离来鉴定 ER 应激期间翻译增加的 mRNA。这项研究的结果预计将揭示真菌 ER 应激的新范例。反应，这可能导致开发新的策略来对抗烟曲霉以及其他利用 UPR 产生毒力的真核病原体的感染。