Hypoxia-induced Responses and Innate Immunity

缺氧引起的反应和先天免疫

基本信息

批准号：
7356036
负责人：
RANDALL Scott JOHNSON
金额：
$ 32.34万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7356036
关键词：
Acute Address Adhesions Affect Apoptosis Appendix Back Bacterial Infections Biological Process Blood Vessels Cell Lineage Cell Survival Cell physiology Cell surface Cells Cellular biology Chemotaxis Chronic Collaborations Communicable Diseases Condition Connective Tissue Diseases Cytokine Gene Data Development Disease Drug Delivery Systems Effector Cell Embryonic Development Endopeptidases Environment Enzymes Gene Targeting Genes Glucose Glycolysis Goals Host Defense Human Hypoxia Immune Immune system In Vitro Infection Infiltration Inflammation Inflammatory Inflammatory Response Intravenous Invasive Investigation Ischemia Journals Knockout Mice Laboratories Lead Link Localized Mediating Mediator of activation protein Medicine Metabolic Metabolic Control Metabolic Pathway Metabolism Microbe Modeling Mouse Strains Mus Myelogenous Myeloid Cells Natural Immunity Nature Necrosis Numbers Oxygen Pathogenesis Pathway interactions Pattern Peptide Hydrolases Phagocytosis Play Predisposition Price Process Production Property Proteins Publications Published Comment Range Reactive Nitrogen Species Reagent Regulation Reliance Reporting Research Respiratory Burst Role Septicemia Skin Soft Tissue Infections Stimulus Streptococcus pyogenes Subcutaneous Tissue System Thrombosis Tissue Cage Tissues Transcriptional Regulation Tumor Suppressor Genes Ubiquitin Vascular Endothelial Growth Factors Vascular Permeabilities anaerobic glycolysis antimicrobial cathelicidin antimicrobial peptide chemokine receptor cytokine cytotoxicity fighting granulocyte in vivo injured interest killings macrophage medical schools microbial migration monocyte multicatalytic endopeptidase complex neutrophil news pathogen recombinase response subcutaneous therapeutic target transcription factor transcytosis

项目摘要

Macrophage and neutrophils are essential for an immediate response to infection as components of the innate immune system, and these cells often function in a hypoxic micro-environment during microbial, and especially bacterial, infection. Our goal is to determine the mechanisms of hypoxic response in myeloid cells during bacterial challenge, through studying the role of the hypoxia-induced transcription factor HIF-1a during that process. The specific aims of this proposal are: Specific aim 1: Determine the role of HIF-1a in regulating the microbial killing functions of myeloid cells; 1a. Analyze the role of HIF-1a in neutrophil and macrophage bacterial killing under normoxic, hypoxic and anoxic conditions; 1b. Determine the role of HIF-1a in neutrophil and macrophage production of the oxidative burst and reactive nitrogen species; 1c. Determine the role of HIF-1a in neutrophil protease activity and the production and activation of cathelicidin antimicrobial peptides; Specific aim 2: Determine the role of HIF-1a in the migratory, survival and immune-activating functions of myeloid cells; 2a. Analyze the role of HIF-1a in neutrophil chemotaxis and endothelial transcytosis under normoxic, hypoxic and anoxic conditions; 2b. Determine the role of HIF-1a in protection of neutrophils and macrophages against bacterial-induced cytotoxicity and apoptosis; 2c. Determine the role of HIF-1a in the pattern of proinflammatory cytokine gene activation in neutrophils and macrophages responding to a bacterial stimulus; Specific aim 3: Determine the function of HIF-1a in innate immune defense against bacterial infection in vivo; 3a. Determine the role of HIF-1a in localized neutrophil migration and killing using a murine subcutaneous tissue cage model; 3b. Determine the role of HIF-1a in restricting systemic spread of infection from a hypoxic focus using a murine subcutaneous infection mode!; 3c. Determine the role of HIF-1a in development and control of bacterial septicemia using a murine intravenous infection model.

巨噬细胞和中性粒细胞对于作为先天免疫系统的成分立即反应感染至关重要，并且这些细胞在微生物（尤其是细菌感染）期间通常在低氧微型环境中起作用。我们的目标是通过研究缺氧诱导的转录因子HIF-1A在此过程中的作用来确定细菌挑战期间髓样细胞中缺氧反应的机制。该提案的具体目的是：具体目标1：确定HIF-1A在调节髓样细胞的微生物杀伤功能中的作用； 1a。分析HIF-1A在常氧，低氧和缺氧条件下的中性粒细胞和巨噬细菌杀死中的作用； 1B。确定HIF-1A在中性粒细胞和巨噬细胞的产生氧化爆发和活性氮种； 1C。确定HIF-1A在中性粒细胞蛋白酶活性以及cathelicidin抗菌肽的产生和激活中的作用；具体目标2：确定HIF-1A在髓样细胞的迁移，生存和免疫激活功能中的作用； 2a。分析HIF-1A在常氧，低氧和缺氧条件下HIF-1A在中性粒细胞趋化性和内皮转胞胞菌中的作用； 2b。确定HIF-1A在保护中性粒细胞和巨噬细胞免受细菌诱导的细胞毒性和凋亡的作用； 2C。确定HIF-1A在促嗜中性粒细胞和巨噬细胞中对细菌刺激反应的促炎细胞因子基因激活模式中的作用；特定目标3：确定HIF-1A在先天免疫中的功能防御体内细菌感染； 3a。确定HIF-1A在局部嗜中性粒细胞迁移中的作用，并使用鼠皮下组织笼模型杀死； 3b。通过使用鼠皮下感染模式来确定HIF-1A在限制从低氧焦点的系统传播中的作用！； 3C。确定HIF-1A使用鼠类静脉感染模型的HIF-1A在细菌败血病的发展和控制中的作用。