VEGF And Renal Inflammation

描述（由申请人提供）：正常的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vegf诱导的丰富血管网络和白细胞运输有关。本提案的总体目标是探索VEGF在肾脏炎症中的新作用。我们已经确定了免疫反应（涉及CD40配体，在活化的T细胞和血小板上表达，以及CD40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CD40。在Specific Aim 1中，将确定CD40信号和VEGF产生之间的机制相互作用。复杂的体外模型将用于定义不同细胞内信号分子的作用，其中Ras在cd40诱导的人血管内皮细胞（HUVEC）和肾近端上皮细胞（RPTEC）中VEGF过表达中的作用尤为重要。cd40诱导VEGF转录激活的机制也将被确定。在Specific Aim 2中，将测量vegf诱导的调节内皮细胞激活反应的促炎信号。具体的转录因子在促进vegf诱导的趋化因子IP-10在HUVEC中的表达中的作用将被解决。在这方面，通过使用嵌合结构，将剖析单个受体的作用。总之，这些实验应该阐明cd40诱导内皮细胞和上皮细胞中VEGF过表达的机制，并探讨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.