VEGF And Renal Inflammation

描述（由申请人提供）： 正常人肾脏表达显著量的血管内皮生长因子（VEGF），其是最有效的血管生成细胞因子，也具有促炎特性。许多炎症性肾脏疾病与VEGF诱导的丰富的血管网络和白细胞运输有关。本研究的总体目标是探索VEGF在肾脏炎症中的新作用。我们已经确定了免疫应答（涉及CD 40配体，表达在活化的T细胞和血小板上，以及CD 40相互作用）和VEGF过表达之间的机制联系。肾内皮细胞和上皮细胞均表达CD 40。在具体目标1中，将确定CD 40信号传导和VEGF产生之间的机制相互作用。复杂的体外模型将被用来定义不同的细胞内信号分子的作用，特别重要的是Ras在CD 40诱导的VEGF在人血管内皮细胞（HUVEC）的过度表达，也在肾近端上皮细胞（RPTEC）。还将确定CD 40诱导的VEGF转录激活的机制。在特定目标2中，将测量调节内皮活化反应的VEGF诱导的促炎信号。特定的转录因子在促进VEGF诱导的趋化因子IP-10在HUVEC中的表达中的作用将得到解决。在这方面，通过使用嵌合构建体，将剖析单个受体的作用。总之，这些实验应该阐明CD 40诱导的VEGF在内皮细胞和上皮细胞中过度表达的机制，并探索VEGF如何通过释放趋化因子促进肾脏炎症。

DESCRIPTION (provided by applicant): The normal human kidney expresses significant amount of vascular endothelial growth factor (VEGF), the most potent angiogenic cytokine, which also has proinflammatory properties. A number of inflammatory kidney diseases are associated with VEGF-induced rich vascular network and leukocyte trafficking. The overall objective of this proposal is to explore a novel role of VEGF in renal inflammation. We have identified a mechanistic link between immune response (involving CD40 ligand, expressed on activated T cells and platelets, and CD40 interactions) and the overexpression of VEGF. The renal endothelial and epithelial cells, both express CD40. In Specific Aim 1, the mechanistic interactions among CD40 signaling and VEGF production will be determined. The sophisticated in vitro models will be utilized to define the role of different intracellular signaling molecules, with special importance to Ras in CD40-induced VEGF overexpression in human vascular endothelial cell (HUVEC), and also in renal proximal epithelial cell (RPTEC). The mechanism of CD40-induced VEGF transcriptional activation will also be determined. In Specific Aim 2, the VEGF-induced proinflammatory signals that regulate endothelial activation responses will be measured. The role of specific transcription factors in promoting VEGF-induced expression of the chemokine IP-10 in HUVEC will be addressed. In this respect, by the use of chimeric constructs, the role of individual receptors will be dissected. Together, these experiments should elucidate the mechanism of CD40-induced VEGF overexpression in endothelial and epithelial cells, and explore how VEGF promotes renal inflammation through the release of chemokines.