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Liver kinase B1 in angiogenesis

肝激酶 B1 在血管生成中的作用

基本信息

批准号：
10058244
负责人：
MING-HUI ZOU
金额：
$ 46.01万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-07 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058244
关键词：
Adaptor Signaling Protein Angiogenic Factor Binding Blood Vessels Cancer Patient Cells Data Development Down-Regulation Endocytosis Endothelial Cells Endothelium Fibrinogen Fibroblast Growth Factor Receptors Genetic Transcription Goals Growth Growth Factor HGF gene Human Implant Injections KDR gene Knock-out Knockout Mice Lung Neoplasms Malignant - descriptor Malignant neoplasm of lung Mediating Mediator of activation protein Messenger RNA Molecular Mus NRP1 gene Neoplasm Metastasis Neoplasms in Vascular Tissue Neuropilin-1 Neuropilins Nude Mice PDGFRB gene Patients Physiologic Neovascularization Platelet-Derived Growth Factor Platelet-Derived Growth Factor alpha Receptor Proteins Resistance STK11 gene Signal Transduction Specificity Structure of parenchyma of lung Transcriptional Activation Tumor Angiogenesis Tumor Suppressor Genes Vascular Endothelial Growth Factors Vascularization angiogenesis bevacizumab cancer cell in vivo lung cancer cell migration mouse model neoplastic cell neutralizing antibody new therapeutic target novel paracrine prevent promoter receptor recruit response restoration subcutaneous targeted treatment trafficking transcription factor tumor tumor growth tumor microenvironment

项目摘要

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.

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产生的以及它们如何影响肿瘤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。

项目成果

期刊论文数量（31）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SNRK (Sucrose Nonfermenting 1-Related Kinase) Promotes Angiogenesis In Vivo.

SNRK（蔗糖非发酵1相关激酶）在体内促进血管生成。

DOI：
10.1161/atvbaha.117.309834
发表时间：
2018-03
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Lu Q;Xie Z;Yan C;Ding Y;Ma Z;Wu S;Qiu Y;Cossette SM;Bordas M;Ramchandran R;Zou MH
通讯作者：
Zou MH

AMP-Activated Protein Kinase γ2 to the Rescue in Ischemic Heart.

AMP 激活的蛋白激酶 γ2 可拯救缺血性心脏。