Liver kinase B1 in angiogenesis

肝激酶 B1 在血管生成中的作用

• 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
• 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

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.

项目概要 最近的证据表明内皮细胞通过血管分泌因子促进肿瘤 生长和转移。了解血管分泌因子的过量程度 产生的以及它们如何影响肿瘤发展可能会揭示新的靶标 疗法。我们令人兴奋的初步数据表明肝激酶 B1 (LKB1) 是一种肿瘤 抑制基因，调节 Neuropilin (NRP)-1 和 VEGF，表明 LKB1 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。该应用的中心假设是 LKB1 在 EC 和肿瘤细胞下调 NRP-1 和其他促血管生成因子（PDGF 和 FGFR）同时抑制 Sp1 诱导的 VEGF 转录激活，从而维持 血管生成和肿瘤生长受到抑制的状态。有三个相互关联的目标 来验证或者反驳这个假设。目标 1 是确定 LKB1 是否会导致 VEGF 通过阻碍转录激活表达，从而改变 生理性血管生成。目标 2 是确定 LKB1 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 LKB1 下调血管生态位中 VEGF 和 NRP-1 的作用 体内。我们完全预计该项目的完成将有助于定义分子 LKB1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） 从而减少肿瘤生长和缺血性血管生成。

项目成果

Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases.

心血管疾病中色氨酸分解代谢的异常犬尿氨酸途径。

• 发表时间: 2017
• 作者: Song, Ping;Ramprasath, Tharmarajan;Wang, Huan;Zou, Ming
• 通讯作者: Zou, Ming

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

SNRK（蔗糖非发酵 1 相关激酶）促进体内血管生成。

• 发表时间: 2018
• 作者: Lu, Qiulun;Xie, Zhonglin;Yan, Chenghui;Ding, Ye;Ma, Zejun;Wu, Shengnan;Qiu, Yu;Cossette, Stephanie M;Bordas, Michelle;Ramchandran, Ramani;Zou, Ming
• 通讯作者: Zou, Ming

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。

• 发表时间: 2017-10-27
• 影响因子: 20.1
• 作者: Ding, Ye;Zou, Ming
• 通讯作者: Zou, Ming

Endothelial cell-specific expression of serine/threonine kinase 11 modulates dendritic cell differentiation.

丝氨酸/苏氨酸激酶 11 的内皮细胞特异性表达调节树突状细胞分化。

• 发表时间: 2022-02-03
• 影响因子: 16.6
• 作者: Zhao, Qiang;Han, Young;Song, Ping;Liu, Zhixue;Yuan, Zuyi;Zou, Ming
• 通讯作者: Zou, Ming

Suppression of m6A mRNA modification by DNA hypermethylated ALKBH5 aggravates the oncological behavior of KRAS mutation/LKB1 loss lung cancer.

DNA 高甲基化 ALKBH5 对 m6A mRNA 修饰的抑制会加剧 KRAS 突变/LKB1 缺失肺癌的肿瘤学行为。

• 发表时间: 2021-05-20
• 影响因子: 9
• 作者: Zhang, Donghong;Ning, Jinfeng;Okon, Imoh;Zheng, Xiaoxu;Satyanarayana, Ganesh;Song, Ping;Xu, Shidong;Zou, Ming
• 通讯作者: Zou, Ming