Role of VEGF and PlGF signaling in sepsis

VEGF 和 PlGF 信号在脓毒症中的作用

基本信息

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
项目类别：
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

项目摘要

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.

我们已经表明，血管内皮生长因子（VEGF）的循环水平和在败血症的小鼠和人类模型中，胎盘生长因子（PLGF）升高， VEGF在败血症中起致病作用，PLGF的上调代表自适应宿主反应可预防败血症的发病率和死亡率。向我们知识，这些数据是第一个证明PLGF的任何生理作用的数据。在 PLGF在败血症中的保护作用，携带酪氨酸激酶缺陷的小鼠 VEGFR1/FLT-1受体显示出内毒素介导的死亡率降低。基于这些调查结果我们假设VEGF和PLGF信号传导之间的平衡很精细是宿主反应的核心，并且失衡会导致病理生理。这总体目标是了解VEGF和PLGF信号在期间如何协调宿主先天免疫反应。 AIM 1是描述VEGF在主机响应中的作用感染。在修订的申请中（为期两年的ARRA奖），我们有将我们的研究重新集中在AIM 1中，以测量动物模型中的VEGFA同工型表达败血症，确定VEGF-B在败血症动物模型中的作用并产生靶向HPRT的小鼠，具有VEGF，VEGFR1，VEGFR2和 SVEGFR1。目标2是描述PLGF在宿主对感染反应中的作用。在修订应用程序，AIM 2专门关注VEGFR1和PLGF-VEGF的角色败血症中的异二聚体。