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: 8675902
• 负责人: KISHORE K WARY
• 金额: $ 32.2万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675902
• 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; Hemorrhage; Investigation; 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 Factor Receptor-2; Vascular Endothelial Growth Factors; analog; angiogenesis; base; cadherin 5; density; design; insight; lipid phosphate phosphatase; lung injury; neoplastic cell; novel; novel therapeutics; outcome forecast; public health relevance; 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，即现有血管形成新血管，是一个基本的生物学过程，不仅需要血管内皮生长因子（VEGF）和VEGF受体-2 （VEGFR2）系统的作用，还需要无翼通路（Wnt）的激活。然而，Wnt信号在血管生成中的潜在机制尚不清楚。R01-HL079356更新的目的是研究脂质磷酸磷酸酶-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，我们描述了LPP3如何促进b-连环蛋白介导的t细胞因子-4/淋巴细胞增强因子-1 （TCF4/ lev -1）靶基因的转录激活。我们发现，磷酸酶紧张素（PTEN）依赖的LPP3激活的b-catenin负责血管内皮(VE)-钙粘蛋白和纤维连接蛋白的合成和沉积，这是细胞-细胞和细胞-基质粘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ECs中Lpp3基因的条件缺失可诱导这些细胞在13.5-14.5胚胎(E)天内凋亡。因此，在这一更新应用中，我们将验证LPP3在血管生成过程中需要抵抗一种或多种促凋亡信号的新假设。AIM#1将概述LPP3调节b-catenin与PTEN的关联以促进细胞周期进程和保护细胞免于凋亡的机制。此外，我们将解决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的假设。我们预测，抑制这种生存途径将促进组织微环境中这些细胞的凋亡，否则固有的凋亡途径是有限的。AIM#2将研究参与肺微血管重构的ECs中Lpp3的定时缺失对气道血管对促凋亡刺激敏感性的影响。这些观察结果将揭示LPP3如何影响成人组织微环境中的细胞存活。本申请中提出的研究将建立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-catenin依赖性细胞存活途径的能力。这些研究结果可能揭示新的治疗策略来调节血管生成，内皮细胞和肿瘤细胞的凋亡特性。