VEGF And Renal Inflammation

描述(申请人提供)：正常人肾脏表达大量的血管内皮生长因子(VEGF)，这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血管内皮生长因子诱导的丰富的血管网络和白细胞的转运有关。这项建议的总体目标是探索血管内皮生长因子在肾脏炎症中的新作用。我们已经确定了免疫反应(包括CD40配体，表达在活化的T细胞和血小板上，以及CD40的相互作用)与血管内皮生长因子的过度表达之间的机制联系。肾内皮细胞和上皮细胞均表达CD40。在具体目标1中，将确定CD40信号和血管内皮生长因子产生之间的机制相互作用。复杂的体外模型将被用来确定不同的细胞内信号分子的作用，特别是在CD40诱导的人血管内皮细胞(HUVEC)和肾近端上皮细胞(RPTEC)中RAS在血管内皮细胞(HUVEC)和肾近端上皮细胞(RPTEC)过表达中的作用。CD40诱导的血管内皮生长因子转录激活的机制也将被确定。在特定的目标2中，将测量调节内皮细胞激活反应的血管内皮生长因子诱导的促炎信号。特定转录因子在促进血管内皮生长因子诱导的HUVEC中趋化因子IP-10表达中的作用将被讨论。在这方面，通过使用嵌合结构，单个受体的作用将被剖析。综上所述，这些实验将阐明CD40诱导内皮细胞和上皮细胞过度表达血管内皮生长因子的机制，并探索血管内皮生长因子是如何通过释放趋化因子来促进肾脏炎症的。

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.