Role of VEGF and PlGF signaling in sepsis

VEGF 和 PlGF 信号在脓毒症中的作用

• 批准号: 7929690
• 负责人: William C Aird
• 金额: $ 37.58万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929690
• 关键词: Animal Model; Animals; Apoptosis; Award; Benefits and Risks; Binding; Biology; Comorbidity; Data; Defense Mechanisms; Distal; Endotoxins; Equilibrium; Foundations; Functional disorder; Goals; Human; Hypoxia; Immune response; Infection; Knowledge; Light; Liver; Lung; Malignant Neoplasms; Measures; Mediating; Modeling; Morbidity - disease rate; Mus; Organ; Outcome; Patients; Physiological; Placental Growth Factor; Play; Pneumonia; Protein Isoforms; Protein Tyrosine Kinase; Risk; Role; Sepsis; Severity of illness; Signal Transduction; Therapeutic; Tyrosine Kinase Domain; Up-Regulation; VEGFA gene; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor B; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; base; insight; monocyte; mortality; mouse model; novel; protective effect; receptor; research study; response; septic; tumor; vascular bed

We have shown that circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are elevated in mouse and human models of sepsis, that VEGF plays a pathogenic role in sepsis, and that the upregulation of PlGF represents an adaptive host response that protects against sepsis morbidity and mortality. To our knowledge, these data are the first to demonstrate any physiological role for PlGF. In spite of the protective role of PlGF in sepsis, mice carrying a tyrosine kinase-deficient VEGFR1/Flt-1 receptor displayed reduced endotoxin-mediated mortality. Based on these findings we hypothesize that a finely tuned balance between VEGF and PlGF signaling is central to the host response and that an imbalance leads to pathophysiology. The overall goal is to understand how VEGF and PlGF signaling is coordinated during the host innate immune response. Aim 1 is delineate the role of VEGF in the host response to infection. In the revised application (for the two-year ARRA award), we have refocused our studies in Aim 1 to measure VEGFA isoform expression in animal models of sepsis, determine the role of VEGF-B in animal models of sepsis and to generate Hprt-targeted mice with inducible over-expression of VEGF, VEGFR1, VEGFR2 and sVEGFR1. Aim 2 is to delineate the role of PlGF in the host response to infection. In the revised application, Aim 2 focuses specifically on the role of VEGFR1 and PlGF-VEGF heterodimers in sepsis.

我们已经证明，循环中血管内皮生长因子（VEGF）和 胎盘生长因子（PlGF）在脓毒症的小鼠和人模型中升高， VEGF在脓毒症中起致病作用，PlGF的上调代表了 适应性宿主反应，防止脓毒症发病率和死亡率。对我们 据了解，这些数据是第一次证明PlGF的任何生理作用。在 尽管PlGF在脓毒症中具有保护作用，但携带酪氨酸激酶缺陷的小鼠 VEGFR 1/Flt-1受体显示内毒素介导的死亡率降低。基于这些 我们假设VEGF和PlGF信号之间的微调平衡 是宿主反应的核心，失衡会导致病理生理学。的 总体目标是了解VEGF和PlGF信号传导在肿瘤生长过程中是如何协调的。 宿主先天免疫反应。目的1探讨VEGF在宿主免疫应答中的作用 感染在修改后的申请（两年期ARRA奖）中，我们有 我将我们的研究重点重新放在目标1中，以测量动物模型中VEGFA同种型的表达 脓毒症，确定VEGF-B在脓毒症动物模型中的作用， 具有VEGF、VEGFR 1、VEGFR 2和VEGFR 3的可诱导过表达的Hprt靶向小鼠 sVEGFR1。目的2是阐明PlGF在宿主感染应答中的作用。在 修订后的申请中，目标2特别关注VEGFR 1和PlGF-VEGF的作用 异二聚体在败血症中的作用。