Liver kinase B1 in angiogenesis

项目摘要 最近的研究表明，内皮细胞通过血管分泌因子促进肿瘤的发生， 生长和转移。了解过量的血管分泌因子 以及它们如何影响肿瘤的发展，可能会揭示新的靶点， 治疗我们令人兴奋的初步数据表明，肝激酶B1（LKB 1），一种肿瘤 抑制基因，调节神经纤毛蛋白（NRP）-1和VEGF，表明LKB 1可能 通过其抑制功能成为血管生成和肿瘤生长的中心介质 NRP-1和VEGF。本申请的中心假设是LKB 1在两种细胞中均 内皮细胞和肿瘤细胞下调NRP-1和其他促血管生成因子（PDGF & FGFR），同时抑制Sp1诱导的VEGF转录激活，从而维持 一种抑制血管生成和肿瘤生长的状态。有三个相互关联的目标 来验证或反驳这个假设目的1是确定LKB 1是否导致降低 VEGF表达通过阻碍转录激活从而改变 生理性血管生成目的2是确定LKB 1是否抑制NRP-1和其他 非VEGF生长因子介导的血管生成。最后，在目标3中，我们将确定 LKB 1下调血管龛内VEGF和NRP-1的作用 in vivo.我们完全期望这个项目的完成将有助于确定分子 LKB 1抑制VEGF转录表达和活性的机制， NRP-1和血管生态位内的其他促血管生成因子（FGFR和PDGFR） 导致肿瘤生长和缺血性血管生成减少。

PROJECT SUMMARY Recent evidence indicates that endothelial cell via angiocrine factors promote tumor growth and metastasis. Understanding how excessive amount of angiocrine factors are produced and how they influence tumor development might unveil novel targets for therapies. Our exciting preliminary data demonstrates Liver Kinase B1 (LKB1), a tumor suppressor gene, regulates Neuropilin (NRP)-1 and VEGF, suggesting that LKB1 may be a central mediator of angiogenesis and tumor growth through its inhibitory function on NRP-1 and VEGF. The central hypothesis of this application is that LKB1 in both ECs and tumor cells down-regulates NRP-1 and other pro-angiogenic factors (PDGF & FGFR) while inhibiting Sp1-induced VEGF transcriptional activation thereby maintaining a state of suppressed angiogenesis and tumor growth. There are three interrelated aims to validate or to refute this hypothesis. Aim 1 is to establish if LKB1 leads to decreased VEGF expression through impeding transcriptional activation hence altering physiological angiogenesis. Aim 2 is to establish if LKB1 suppresses NRP-1 and other non-VEGF growth factors-mediated angiogenesis. Finally, in Aim 3, we will determine the contribution of LKB1 down-regulation of VEGF and NRP-1 within the vascular niche in vivo. We fully anticipate the completion of this project will help define the molecular mechanism by which LKB1 suppresses transcriptional expression and activity of VEGF, NRP-1, and other pro-angiogenic factors (FGFR & PDGFR) within the vascular niche resulting in a reduction in tumor growth and ischemic angiogenesis.