Role of STIM1 in E. coli Pneumonia

STIM1 在大肠杆菌肺炎中的作用

• 批准号: 8815359
• 负责人: Hongwei Gao
• 金额: $ 20.78万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815359
• 关键词: 1,2-diacylglycerol; Agonist; Alcoholism; Alveolar; Alveolar Macrophages; Alveolitis; Autoimmune hemolytic anemia; Back; Bacteria; Binding; Bronchoalveolar Lavage Fluid; CCAAT-Enhancer-Binding Proteins; CCL2 gene; Ca(2+)-Transporting ATPase; Calcium; Calcium Channel; Cell membrane; Cell model; Cell physiology; Cells; Chronic Obstructive Airway Disease; Clinical; Communities; Data; Dental Enamel; Development; Diabetes Mellitus; Diglycerides; Disease; Endoplasmic Reticulum; Epithelial Cells; Escherichia coli; Escherichia coli Infections; G Protein-Coupled Receptor Genes; Gene Deletion; Gene Expression; Genetic study; Hepatosplenomegaly; Homeostasis; Host Defense; Human; Hydrolysis; Immune; Immune response; Immunity; Immunocompetent; Immunocompromised Host; Immunologic Deficiency Syndromes; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Ion Channel Protein; Knowledge; Lung; Lung Inflammation; Mediating; Mediator of activation protein; Membrane; Molecular; Morbidity - disease rate; Mus; Muscle hypotonia; Myelogenous; Myeloid Cells; Nosocomial pneumonia; Pathogenesis; Patients; Phosphatidylinositol 4,5-Diphosphate; Play; Pneumonia; Point Mutation; Proteins; Pump; Recruitment Activity; Role; STIM1 gene; Signal Transduction; Signaling Molecule; Site; Stimulus; System; Testing; Thrombocytopenia; Toll-like receptors; Work; base; design; extracellular; human STIM1 protein; in vivo; inflammatory lung disease; lung injury; macrophage; mortality; neutrophil; new therapeutic target; novel; postnatal; protein activation; public health relevance; receptor; recombinase; response; sensor; transcription factor

DESCRIPTION (provided by applicant): Escherichia coli (E. coli) is one of the major causes of nosocomial pneumonia. Moreover, E. coli pneumonia may also be community-acquired in patients who have underlying disease such as diabetes mellitus, alcoholism, and chronic obstructive pulmonary disease. Although inappropriate inflammatory host responses play a central role in the pathogenesis of pneumonia, the precise molecular mechanisms underlying the development of this disorder remain poorly understood. Altered calcium homeostasis is considered to play an important role in inflammation. Although the predominant mechanisms to raise intracellular calcium used by most immune cells is store-operated Ca2+ entry (SOCE) whereby the depletion of endoplasmic reticulum (ER) Ca2+ stores triggers the influx of extracellular Ca2+, the direct molecular basis of SOCE activation was unknown until the recent identification of stromal interaction molecule 1 (STIM1) as the critical ER Ca2+ sensor. However, the significance of STIM1 and SOCE in in vivo inflammatory responses, immunity to infection, and other immune-related diseases remains largely unknown. Using the Cre recombinase-loxP system, we recently generated mice with specific deletion of the gene encoding STIM1 in myeloid cells (STIM1-/-). Our preliminary data indicate that STIM1 deficiency significantly reduced E. coli-induced IL-6, KC, IL-1b, and MCP-1 levels in bronchoalveolar lavage (BAL) fluids and neutrophil accumulation in the lung compared to WT mice (STIM1+/+). Furthermore, E. coli-stimulated STIM1-/- mice showed significantly reduced lung transcription factors CCAAT/enhancer-binding proteins (C/EBPs) activation (mainly C/EBP�). We further show that STIM1 interacts with Orai1 and TRPC1, important Ca2+ channels for SOCE in immune cells. Based on these studies, we hypothesize that STIM1 plays an important regulatory role in lung inflammatory responses to E. coli and host defense against E. coli pneumonia by interacting with Orai1, TRPC1, and other signaling molecules. Therefore, this exploratory study is designed to define the roles of STIM1 in E. coli- induced pulmonary alveolitis and the underlying molecular mechanisms. Two specific aims are proposed to test our hypothesis. In the first aim, we will determine the role of STIM1 in the lungs against E. coli infection. In the second aim, we will elucidate the molecular mechanisms of STIM1 function in the E. coli pneumonia. The results of our studies are expected to provide important novel information on the regulatory roles of STIM1 in the lung inflammatory responses to bacteria. This knowledge will represent a new paradigm for approaching the development of novel therapeutic targets for treatment of pneumonia.

性状（由申请人提供）：大肠杆菌（E.大肠杆菌）是医院内肺炎的主要原因之一。此外，E.大肠杆菌肺炎也可能是社区获得性的患者谁有潜在的疾病，如糖尿病，酗酒，慢性阻塞性肺病。虽然不适当的炎症宿主反应在肺炎的发病机制中起着核心作用，但这种疾病发展的确切分子机制仍然知之甚少。钙稳态改变被认为在炎症中起重要作用。尽管大多数免疫细胞使用的提高细胞内钙的主要机制是钙库操纵的钙内流（SOCE），其中内质网（ER）钙库的耗尽触发细胞外钙的内流，但是直到最近鉴定基质相互作用分子1（STIM 1）作为关键的ER钙传感器，SOCE激活的直接分子基础才被知晓。然而，STIM 1和SOCE在体内炎症反应、感染免疫和其他免疫相关疾病中的重要性在很大程度上仍然未知。使用Cre重组酶-loxP系统，我们最近产生了骨髓细胞中编码STIM 1的基因特异性缺失的小鼠（STIM 1-/-）。我们的初步数据表明，STIM 1缺陷显着降低E。与WT小鼠（STIM 1 +/+）相比，支气管肺泡灌洗液（BAL）中大肠杆菌诱导的IL-6、KC、IL-1b和MCP-1水平以及肺中的中性粒细胞蓄积。此外，E.大肠杆菌刺激的STIM 1-/-小鼠显示肺转录因子CCAAT/增强子结合蛋白（C/EBP）激活（主要是C/EBP）显著减少。我们进一步表明，STIM 1与Orai 1和TRPC 1相互作用，这是免疫细胞中SOCE的重要Ca 2+通道。基于这些研究，我们推测STIM 1在E.大肠杆菌和宿主对E.大肠杆菌肺炎通过与Orai 1，TRPC 1和其他信号分子相互作用。因此，本研究旨在探讨STIM 1在大肠杆菌中的作用。大肠杆菌致肺泡炎的分子机制。提出了两个具体的目标来检验我们的假设。在第一个目标中，我们将确定STIM 1在肺中对抗E.大肠杆菌感染。第二个目标是阐明STIM 1在大肠杆菌中的分子机制。大肠杆菌肺炎。我们的研究结果有望为STIM 1在细菌致肺部炎症反应中的调节作用提供重要的新信息。这些知识将代表一种新的范式，用于接近开发新的治疗靶点治疗肺炎。