Ehrilchiacidal Mechanisms In Leukocytes

白细胞中的埃里希酸机制

基本信息

批准号：
7173720
负责人：
YASUKO RIKIHISA
金额：
$ 31.89万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-08-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7173720
关键词：
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one Adam11 gene Address Anabolism Anaplasma phagocytophilum Animals Apoptosis Bacteria Binding Sites Blood CCL22 gene Caspase Cell membrane Cell-Free System Cells Cholesterol Cholesterol Esters Condition Cultured Cells Ehrlichia chaffeensis Ehrlichiosis Emerging Communicable Diseases Environment Enzymes Event Excision Family Family member Funding GPI Membrane Anchors GTPase-Activating Proteins Gene Family Genes Goals Holoenzymes Human In Vitro Infection Infection prevention Integration Host Factors Interferons Iron Knowledge Leukocytes Lipid A Lipopolysaccharides Membrane Membrane Microdomains Messenger RNA Mitochondria Modeling Mus NADP NADPH Oxidase Pharmaceutical Preparations Phospholipase Prevention Prevention strategy Protein Family Protein Tyrosine Kinase Proteins Reducing Agents Research Research Personnel Signal Pathway Signal Transduction Signaling Molecule Site Specificity Testing Ticks Transcriptional Regulation Transglutaminases Tyrosine Tyrosine Phosphorylation United States National Institutes of Health caveolin 1 cell type chlorambucil/dactinomycin/methotrexate protocol comparative cytochrome b558 expression vector human granulocytic ehrlichiosis inhibitor/antagonist intracellular parasitism killings monocyte mouse model neutrophil novel novel therapeutics pathogen prevent programs transglutaminase 1

项目摘要

DESCRIPTION (provided by applicant): Ehrlichia chaffeensis and Anaplasma phagocytophilum cause emerging infectious diseases, human monocytic ehrlichiosis (HME) and human granulocytic ehrlichiosis (HGE), respectively. The overall goal of the proposed study is to identify ehrlichiacidal mechanisms in the host cells, by focusing host signaling events essential (not just parallel phenomena) for intracellular parasitism. Thus, mechanisms can be potentially exploited to prevent and treat these infections. During the previous funding period this project identified several novel signaling pathways and mechanisms essential for E. chaffeensis and A. phagocytophilum infection. Blocking the host signals effectively killed these bacteria without harming the host human leukocytes in vitro. In this renewal proposal we will: 1. Elucidate mechanisms by which TG, GPI-anchored proteins, and tyrosine phosphorylated proteins are required for E. chaffeensis and A. phagocytophilum by identifying proteins involved by MALDI-TOF analysis, the gene knockdown, and immunolabeling. 2. Evaluate influences of cholesterol levels on mouse models of HGE and HME, and influences of cholesterol derivatives from ticks on E. chaffeensis and A. phagocytophilum infectivity. 3. Elucidate the mechanism by which A. phagocytophilum and E. chaffeensis block host cell NADPH oxidase activation in a cell-free system and COS-phox cells. 4. Elucidate the mechanism by which A. phagocytophilum inhibits human neutrophil apoptosis by analysis of caspases, bcl-2 family, and the mitochondrial integrity, transcriptional regulation of bcl-2 family proteins. The information to be obtained from the proposed study will point to unique mechanisms to kill E. chaffeensis and A. phagocytophilum and contribute to our understanding on host factors and signals induced by these pathogens and are essential for the obligatory intracellular parasitism. The results may point to a potential target for new treatment and prevention of HME and HGE.

描述（由申请人提供）：恰菲埃利希体和嗜吞噬细胞无形体分别引起新发传染病，人单核细胞埃利希体病（HME）和人粒细胞埃利希体病（HGE）。拟议研究的总体目标是通过关注细胞内寄生所必需的宿主信号事件（不仅仅是平行现象）来确定宿主细胞中的埃里希酸机制。因此，可以潜在地利用机制来预防和治疗这些感染。在上一个资助期间，该项目确定了查菲埃里希菌和嗜吞噬细胞球菌感染所必需的几种新的信号传导途径和机制。阻断宿主信号可以有效杀死这些细菌，而不会在体外损害宿主人类白细胞。在此更新提案中，我们将： 1. 通过鉴定 MALDI-TOF 分析、基因敲低和免疫标记所涉及的蛋白质，阐明查菲埃里希菌和嗜吞噬细胞球菌所需的 TG、GPI 锚定蛋白和酪氨酸磷酸化蛋白的机制。 2. 评估胆固醇水平对HGE和HME小鼠模型的影响，以及蜱胆固醇衍生物对查菲埃里希菌和嗜吞噬细胞球菌感染性的影响。 3. 阐明A. phagocytophilum和E. chaffeensis在无细胞系统和COS-phox细胞中阻断宿主细胞NADPH氧化酶激活的机制。 4. 通过分析caspases、bcl-2家族以及bcl-2家族蛋白的线粒体完整性、转录调控，阐明A. phagocytophilum抑制人中性粒细胞凋亡的机制。从拟议的研究中获得的信息将指出杀死查菲埃里希菌和嗜吞噬细胞菌的独特机制，并有助于我们了解这些病原体诱导的宿主因素和信号，并且对于强制性细胞内寄生至关重要。这些结果可能为 HME 和 HGE 的新治疗和预防指明潜在目标。