Regulation of Wnt signaling by LPP3 (PAP2b) during angiogenesis

血管生成过程中 LPP3 (PAP2b) 对 Wnt 信号传导的调节

• 批准号: 9070495
• 负责人: KISHORE K WARY
• 金额: $ 32.86万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070495
• 关键词: Address; Adherens Junction; Adult; Affect; Apoptosis; Apoptotic; Biological Process; Biology; Blood Vessels; Cardiovascular Diseases; Cell Cycle Progression; Cell Proliferation; Cell Survival; Cell-Matrix Junction; Cells; Cellular biology; Deposition; Diagnosis; Disease; Edema; Embryo; Embryonic Development; Endothelial Cells; Event; Exposure to; Failure; Fibronectins; Funding; Gene Targeting; Genes; Goals; Health; Hemorrhage; Investigation; KDR gene; Lipids; Lung; Malignant Neoplasms; Mediating; Microvascular Permeability; Modeling; Molecular; Molecular Target; Mus; Pathologic Neovascularization; Pathway interactions; Permeability; Phenotype; Phosphatidate Phosphatase; Phosphoric Monoester Hydrolases; Property; Protein Dephosphorylation; Regulation; Role; Signal Pathway; Signal Transduction; Stimulus; System; T cell factor 4; TCF Transcription Factor; TNF gene; Tamoxifen; Testing; Time; Tissues; Transcriptional Activation; Transgenic Mice; Vascular Endothelial Growth Factors; analog; angiogenesis; base; cadherin 5; density; design; insight; lipid phosphate phosphatase; lung injury; neoplastic cell; novel; novel therapeutic intervention; outcome forecast; research study; response; sphingosine 1-phosphate; subcutaneous; tensin

DESCRIPTION (provided by applicant): Angiogenesis, the formation of new blood vessels from existing blood vessels, is a fundamental biological process that requires not only the action of vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR2) system, but also activation of the wingless (Wnt) pathway. However, the underlying mechanisms of Wnt signaling in angiogenesis are not clear. The goal of the renewal of R01-HL079356 is to examine how lipid phosphate phosphatase-3 (LPP3), previously called phosphatidic acid phosphatase-2b (PAP2b), regulates the angiogenic phenotypes of endothelial cells (ECs). In the previous funding cycle, we characterized how LPP3 promotes b-catenin- mediated transcriptional activation of T-cell factor-4/lymphoid enhancer factor-1 (TCF4/LEF-1) target genes. We showed that phosphatase tensin (PTEN)-dependent LPP3 activation of b-catenin was responsible for the synthesis and deposition of vascular endothelial (VE)-cadherin and fibronectin, which are key regulators of cell-cell and cell-matrix adhesion events. Notably, we have determined that Tie-2Cre- mediated conditional deletion of the Lpp3 gene in ECs induces apoptosis of these cells in 13.5-14.5 embryonic (E) days. Therefore, in this renewal application, we will test the novel hypothesis that LPP3 is required to resist one or more pro-apoptotic signals during angiogenesis. AIM#1 will outline studies to characterize the mechanisms whereby LPP3 regulates the association of b-catenin with PTEN to promote cell-cycle progression and protect cells from apoptosis. In addition, we will address the hypothesis that the ability of the LPP3/PTEN/b-catenin signaling module to promote cell survival is critical for angiogenesis. We predict that suppression of this survival pathway will promote apoptosis of these cells in tissue microenvironments where the intrinsic apoptotic pathway is otherwise limiting. AIM#2 will investigate the effect of timed deletion of Lpp3 in ECs involved in lung microvessel remodeling on the sensitivity of airway vasculature to pro-apoptotic stimuli. These observations will reveal how LPP3 influences cell survival in the microenvironments of adult tissue. The studies proposed in this application will establish a molecular basis to support our hypothesis that the angiogenic phenotypes of ECs depend on the ability of these cells to sense the LPP3-mediated b-catenin-dependent cell survival pathway. The results of these investigations may reveal new therapeutic strategies to regulate angiogenesis, and the apoptotic properties of endothelial and tumor cells.

描述(申请人提供)：血管生成，即从现有血管形成新的血管，是一个基本的生物过程，不仅需要血管内皮生长因子(VEGF)和血管内皮生长因子受体2(VEGFR2)系统的作用，还需要激活无翼(Wnt)途径。然而，Wnt信号在血管生成中的潜在机制尚不清楚。更新R01-HL079356的目的是研究脂质磷酸酶-3(LPP3)，以前称为磷脂酸磷酸酶-2b(PAP2b)如何调节内皮细胞(ECs)的血管生成表型。在之前的资助周期中，我们研究了LPP3如何促进b-连环蛋白介导的T细胞因子-4/淋巴增强因子-1(TCF4/Lef-1)靶基因的转录激活。我们发现，依赖于磷酸酶张力蛋白(PTEN)的LPP3激活的b-连环蛋白负责合成和沉积血管内皮细胞(VE)-钙粘附素和纤维连接蛋白，它们是细胞-细胞和细胞-基质黏附事件的关键调节因子。值得注意的是，我们已经确定，Tie-2Cre介导的内皮细胞Lpp3基因的条件缺失在13.5-14.5天胚胎(E)内诱导这些细胞凋亡。因此，在这一新的应用中，我们将测试新的假设，即LPP3在血管生成过程中需要抵抗一个或多个促凋亡信号。目的#1将概述LPP3调节b-连环蛋白与PTEN结合以促进细胞周期进程和保护细胞免受凋亡的机制。此外，我们还将提出假设，即LPP3/PTEN/b-catenin信号模块促进细胞存活的能力对血管生成至关重要。我们预测，抑制这一生存途径将促进这些细胞在组织微环境中的凋亡，而组织微环境中固有的凋亡途径是有限的。目的#2研究Lpp3在参与肺微血管重塑的内皮细胞中定时缺失对气道血管对促凋亡刺激的敏感性的影响。这些观察将揭示LPP3如何影响成人组织微环境中的细胞存活。这项应用中提出的研究将建立一个分子基础来支持我们的假设，即内皮细胞的血管生成表型取决于这些细胞感知LPP3介导的b-连环蛋白依赖的细胞生存途径的能力。这些研究的结果可能揭示新的治疗策略，以调节血管生成，以及内皮细胞和肿瘤细胞的凋亡特性。

项目成果

Integrin α6β1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells.

• DOI: 10.1002/stem.1974
• 发表时间: 2015-06
• 期刊: STEM CELLS
• 影响因子: 5.2
• 作者: Toya, Sophie P.;Wary, Kishore K.;Mittal, Manish;Li, Fei;Toth, Peter T.;Park, Changwon;Rehman, Jalees;Malik, Asrar B.
• 通讯作者: Malik, Asrar B.

Requirement of alpha(4)beta(1) and alpha(5)beta(1) integrin expression in bone-marrow-derived progenitor cells in preventing endotoxin-induced lung vascular injury and edema in mice.

• DOI: 10.1002/stem.241
• 发表时间: 2009-12
• 期刊: STEM CELLS
• 影响因子: 5.2
• 作者: Wary, Kishore K.;Vogel, Stephen M.;Garrean, Sean;Zhao, Yidan D.;Malik, Asrar B.
• 通讯作者: Malik, Asrar B.

Low-dose 6-bromoindirubin-3'-oxime induces partial dedifferentiation of endothelial cells to promote increased neovascularization.

• DOI: 10.1002/stem.1658
• 发表时间: 2014-06
• 期刊: STEM CELLS
• 影响因子: 5.2
• 作者: Kohler, Erin E.;Baruah, Jugajyoti;Urao, Norifumi;Ushio-Fukai, Masuko;Fukai, Tohru;Chatterjee, Ishita;Wary, Kishore K.
• 通讯作者: Wary, Kishore K.

Induced Pluripotent Stem (iPS) Cell Culture Methods and Induction of Differentiation into Endothelial Cells.

诱导多能干（IPS）细胞培养方法以及将分化诱导为内皮细胞。

• DOI: 10.1007/7651_2015_203
• 发表时间: 2016
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Chatterjee I;Li F;Kohler EE;Rehman J;Malik AB;Wary KK
• 通讯作者: Wary KK

Flk1+ and VE-cadherin+ endothelial cells derived from iPSCs recapitulates vascular development during differentiation and display similar angiogenic potential as ESC-derived cells.

• DOI: 10.1371/journal.pone.0085549
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kohler EE;Wary KK;Li F;Chatterjee I;Urao N;Toth PT;Ushio-Fukai M;Rehman J;Park C;Malik AB
• 通讯作者: Malik AB