Establishment of a mouse model for the induction of preeclampsia by soluble VEGFR-1/flt-1 and its modulation by exogenous treatment with antibodies and receptor ligands

可溶性VEGFR-1/flt-1诱导子痫前期小鼠模型的建立及其通过抗体和受体配体外源治疗的调节

• 批准号: 29241972
• 负责人: Dr. Herbert A. Weich
• 金额: --
• 依托单位: Forschungsschwerpunkt Immunantwort und -interventionen
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2006-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/29241972?language=en
• 关键词: Establishment; mouse; model; induction; preeclampsia

Our work hypothesis during the last 24 months was that VEGF-A together with PIGF must be very well regulated and that intratissual balance between sFlt-1 and VEGF/PIGF levels seems to play a crucial role for maintaining vascular homeostasis and that dysregulation of this balance is involved in several vascular diseases. This increasing levels of sFlt-1 secreted from placenta into the maternal blood are associated with decreasing circulating levels of free VEGF-A and PIGF and results in endothelial dysfunction in vivo. In the last period we have sucessfully established a mouse model for preeclampsia using adenoviral overexpression for sFlt-1 in Balb/c mice. This was achieved by intravenous injection of 2.5-5 x108 virus particles into the tail vein of 8-11 week old animals. After 8-10 days animals were sacrified and the glomeruli of the kidney were analyzed by histochemical analysis. Soluble flt-1 overexpression leads to a collapse of microvessels and tubes indicated by a strong reduction of microvessel lumen in a glomerulus. Injection of adenovirus also lead to a massive increase in liver volumen of virus treated animals, indicating that most of the injected virus particles were localized in the liver. So far parameter like blood pressure and proteinuria were not investigated in detail. In order to modulate the pathological effect in the kidney we have started to develop blocking antibodies by phage-display. Because this is a high risk part of the project, we were able to recrute blocking antibodies for flt-1 from a collaborating group. The sflt-1 effect induced for kidney dysfunction will now be analyzed in the last period in great detail. For this purpose we will also start a collaboration to measure induction of high blood pressure by telemetry and want to investigate our question, if blocking antibody to flt-1 can modulate the effect of preeclampsia experimentally induced in mice.

在过去的24个月里，我们的工作假设是VEGF- a和PIGF必须得到很好的调节，sFlt-1和VEGF/PIGF水平之间的组织内平衡似乎对维持血管稳态起着至关重要的作用，这种平衡的失调与几种血管疾病有关。从胎盘分泌到母体血液中的sFlt-1水平的增加与游离VEGF-A和PIGF循环水平的降低有关，并导致体内内皮功能障碍。在过去的一段时间里，我们利用腺病毒在Balb/c小鼠中过表达sFlt-1成功地建立了子痫前期小鼠模型。这是通过将2.5-5 × 108病毒颗粒静脉注射到8-11周龄动物的尾静脉来实现的。8-10 d后处死动物，用组织化学方法分析肾小球。可溶性flt-1过表达导致肾小球微血管和管的塌陷，表现为微血管管腔的强烈减少。注射腺病毒也导致病毒处理动物的肝脏体积大量增加，这表明大多数注射的病毒颗粒都局限于肝脏。到目前为止，血压和蛋白尿等参数还没有详细的研究。为了调节肾脏的病理作用，我们已经开始通过噬菌体展示来开发阻断抗体。因为这是项目的高风险部分，我们能够从一个合作小组中招募flt-1的阻断抗体。sflt-1对肾功能障碍的影响将在最后一期进行详细分析。为此，我们也将开始合作，通过遥测测量高血压的诱导，并想调查我们的问题，如果阻断抗体flt-1可以调节小鼠实验诱导的子痫前期的影响。