权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Coxiella burnetii Subversion of Host Nrf2 Antioxidant Signaling- Resubmission

伯氏柯克斯体颠覆宿主 Nrf2 抗氧化信号 - 重新提交

基本信息

批准号：
10056597
负责人：
Daniel E Voth
金额：
$ 22.4万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056597
关键词：
Acute Acute Disease Alveolar Macrophages Anti-Bacterial Agents Antioxidants Apoptosis Area Autophagosome Binding Proteins Biochemical Biological Assay Cell Death Cell Nucleus Cell Survival Cell model Cells Cellular Stress Cellular Stress Response Chronic Coxiella burnetii Cytoplasmic Protein Cytosol Disease Disease Progression Endocarditis Eukaryotic Cell Event Gene Expression Growth Human Infection Investigation Lysosomes Mediating Modeling Oxidative Stress Parasites Pathway interactions Phosphorylation Prevention Process Proteins Publishing Q Fever Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Small Interfering RNA Testing Type IV Secretion System Pathway Vacuole Virulent biological adaptation to stress design flu in vivo inhibitor/antagonist insight macrophage novel pathogen pathogenic bacteria prevent receptor recruit response trafficking transcription factor

项目摘要

Coxiella burnetii is the intracellular bacterial agent of human Q fever, an acute flu-like illness that can present as potentially fatal chronic endocarditis. Mechanisms used by C. burnetii to parasitize human macrophages remain a mystery. However, through the use of other cell models, studies have demonstrated that C. burnetii regulates numerous host processes, including vesicular trafficking and apoptosis. The current proposal is designed to define mechanisms used by C. burnetii to avoid the oxidative stress response of human alveolar macrophages, which are the pathogen’s target cell in vivo. We found that C. burnetii triggers activation of the cargo receptor p62 and potentially uses this versatile protein to activate the antioxidant transcription factor Nrf2. Aim 1 is designed to define the mechanism by which p62 activates Nrf2. Aim 2 will define the downstream impact of Nrf2 activation on C. burnetii prevention of the oxidative stress response and apoptosis. Throughout the proposal, we will use our primary human alveolar macrophage model of infection to identify disease relevant processes. Collectively, the aims in the current proposal will provide needed insight into the mechanisms used by C. burnetii to parasitize human macrophages, which is a prerequisite for progression of Q fever.

伯内特柯克斯体是人类 Q 热的细胞内细菌病原体，Q 热是一种急性流感样疾病，可导致表现为潜在致命的慢性心内膜炎。 C. burnetii 寄生人类的机制巨噬细胞仍然是一个谜。然而，通过使用其他细胞模型，研究已经表明 C. burnetii 调节许多宿主过程，包括囊泡运输和细胞凋亡。当前提案旨在定义 C. burnetii 使用的机制，以避免人类肺泡巨噬细胞的氧化应激反应，这是病原体的体内靶细胞。我们发现 C. burnetii 触发货物受体 p62 的激活和潜在地利用这种多功能蛋白质来激活抗氧化转录因子 Nrf2。目标 1 是旨在定义 p62 激活 Nrf2 的机制。目标 2 将定义下游 Nrf2 激活对 C. burnetii 预防氧化应激反应和细胞凋亡的影响。在整个提案中，我们将使用我们的初级人类肺泡巨噬细胞感染模型来识别疾病相关过程。总的来说，当前提案的目标将提供需要深入了解 C. burnetii 寄生人类巨噬细胞的机制，这是Q热进展的先决条件。