Hypoxia-induced Responses and Innate Immunity

缺氧引起的反应和先天免疫

• 批准号: 6918864
• 负责人: RANDALL Scott JOHNSON
• 金额: $ 29.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/6918864
• 关键词: DNA binding protein; Streptococcus pyogenes; antigen presentation; bacteria infection mechanism; bacterial disease; cell death; cell migration; chemotaxis; cytokine; gene induction /repression; genetically modified animals; hypoxia inducible factor 1; immune response; immunogenetics; laboratory mouse; leukocyte oxidative burst; macrophage; membrane activity; myeloid stem cell; neutrophil; tissue /cell culture; transcription factor; vascular endothelial growth factors

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作为先天免疫系统的组成部分，对感染的即时反应是必不可少的，这些细胞通常在微生物，特别是细菌感染的缺氧微环境中起作用。我们的目标是通过研究缺氧诱导的转录因子HIF-1a在这一过程中的作用，确定骨髓细胞在细菌攻击过程中缺氧反应的机制。本提案的具体目的是：具体目的1：确定HIF-1a在调节髓细胞的微生物杀伤功能中的作用；1一个。分析HIF-1a在常氧、低氧和缺氧条件下嗜中性粒细胞和巨噬细胞细菌杀伤中的作用；1 b。确定HIF-1a在