权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

SIGNALING MECHANISMS IN REGULATION OF TUMOR ANGIOGENESIS

肿瘤血管生成调节的信号机制

基本信息

批准号：
8279120
负责人：
Dominic E. Cosgrove
金额：
$ 26.45万
依托单位：
FATHER FLANAGAN'S BOYS' HOME
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8279120
关键词：
Adenoviruses Affect Angiogenesis Inhibitors Angiogenic Factor Apoptosis Apoptotic Applications Grants Baculovirus Expression System Basement membrane Binding Binding Sites Biochemical Pathway Blood Blood Vessels C-terminal Catabolism Catalytic Domain Cause of Death Cell Culture System Cell Culture Techniques Cell Proliferation Cell surface Cells Cessation of life Co-Immunoprecipitations Collagen Type IV Colon Carcinoma Complex Data Development Disease Endothelial Cells Extracellular Matrix Fibroblast Growth Factor 2 Gelatinase A Goals Immunoblotting Immunohistochemistry Integrins Investigation Laboratories Life Lung MAP Kinase Gene MMP14 gene Malignant Neoplasms Mediating Mitochondria Modeling Molecular Molecular Target Mus PTGS2 gene PTK2 gene Pathway interactions Phase Phosphorylation Plasma Platelet-Derived Growth Factor Proliferating Proteins Regulation Role Signal Pathway Signal Transduction Solid Neoplasm Stream Testing Therapeutic Transgenic Mice Tumor Angiogenesis Tumor Necrosis Factor Ligand Superfamily Member 6 Up-Regulation Vascular Endothelial Growth Factors Work angiogenesis base bevacizumab cancer type caspase-3 in vivo inhibitor/antagonist insight matrigel migration mouse model proMMP-2 public health relevance therapeutic target tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Cancer is currently one of the most prevalent causes of death in the U.S.A. A major therapeutic option aims to slow the progression of cancer (example: use of anti-VEGF in colon cancer). Therefore, a renewed effort must be made to identify relevant molecular pathways, which could be exploited as therapeutic targets. Progression of many types of cancers is associated with up-regulation of several proangiogenic factors (HIF- 1a, VEGF, bFGF, PDGF, and MMP's etc.) which promotes tumor angiogenesis. These angiogenic factors activate different signaling pathways that regulate cell proliferation, migration and apoptosis. The long-term goals of my laboratory aims to understand the complex signaling mechanisms of angioinhibitors from extracellular matrix (type IV collagen NC1 domains, which are normally present in the blood), and to determine their role in antiangiogenic signaling. Recently my laboratory determined that a1(IV)NC1 mediates multiple signaling mechanisms to regulate tumor angiogenesis. However, its complex influences on tumor- angiogenesis and tumor growth are far from being fully understood. The present grant proposal is specifically directed at elucidating the mechanism whereby a1(IV)NC1 inhibits expression of the pro-angiogenic molecules, and its role in inhibition of tumor growth. In this study we aim to test our hypothesis: "a1(IV)NC1 promotes endothelial cell apoptosis through a1¿1 integrin and inhibits MMP-2 activation through an integrin independent pathway. These activities are critical for the antiangiogenic and antitumorogenic activity of a1(IV)NC1". Towards this end, we have generated an a1(IV)NC1 transgenic mouse model and adenoviruses, cloned and expressed a1(IV)NC1 in the baculovirus expression system and will use this protein for studies outlined in the specific aims. (1) Investigate the angioinhibitory signaling mechanisms by which a1(IV)NC1 inhibits the expression of angiogenic factors, including investigation of possible biochemical pathways. (2) Investigate the complex interactions between a1(IV)NC1/MMP-2 and identify the complementary binding sites involved in this interaction and function. (3) To investigate inhibition of tumor growth by a1(IV)NC1 in a1-integrin null and a1(IV)NC1 transgenic mice. The above Specific aims will be accomplished using cell cultures, a1 integrin null, a1(IV)NC1 transgenic mice and adenoviruses harboring a1(IV)NC1 domain expression cassettes. We will analyze these models using immunoblotting, co-immunoprecipitation, immunohistochemistry, Matrigel plug, and tumor studies. Successful completion of the proposed work will provide valuable insights that may facilitate the development of new antiangiogenic tumor therapies. PUBLIC HEALTH RELEVANCE: Cancer is currently one of the most prevalent causes of death in the USA, and current therapeutic options aim only to slow the progression of cancer. Therefore, a renewed effort must be made to identify nontoxic endogenous circulating anticancer molecules which could be exploited as therapeutic targets. My laboratory has cloned and expressed one such circulating molecule, and is presently testing it in a cell culture system and in live mice having tumors. The data being developed from these proposed studies have potential applications to cure solid tumor growth (cancers) in which angiogenesis contributes to the disease phase.

描述（由申请人提供）：癌症目前是美国最普遍的死亡原因之一，主要的治疗选择旨在减缓癌症的进展（例如：在结肠癌中使用抗vegf）。因此，必须重新努力确定相关的分子途径，这些途径可以作为治疗靶点加以利用。许多类型癌症的进展与几种促进肿瘤血管生成的促血管生成因子（HIF- 1a、VEGF、bFGF、PDGF和MMP等）的上调有关。这些血管生成因子激活不同的信号通路，调节细胞增殖、迁移和凋亡。我实验室的长期目标是了解细胞外基质（IV型胶原NC1结构域，通常存在于血液中）血管抑制剂的复杂信号传导机制，并确定它们在抗血管生成信号传导中的作用。最近，我的实验室发现a1(IV)NC1介导多种信号机制来调节肿瘤血管生成。然而，其对肿瘤血管生成和肿瘤生长的复杂影响尚不完全清楚。目前的拨款提案专门针对阐明a1(IV)NC1抑制促血管生成分子表达的机制，及其在抑制肿瘤生长中的作用。在这项研究中，我们旨在验证我们的假设：“a1(IV)NC1通过a1¿1整合素促进内皮细胞凋亡，并通过整合素不依赖的途径抑制MMP-2的激活。这些活性对于a1(IV)NC1的抗血管生成和抗肿瘤活性至关重要。为此，我们建立了a1(IV)NC1转基因小鼠模型和腺病毒，克隆并在杆状病毒表达系统中表达a1(IV)NC1，并将该蛋白用于具体目标中概述的研究。(1)研究a1(IV)NC1抑制血管生成因子表达的血管抑制信号机制，包括可能的生化途径。(2)研究a1(IV)NC1/MMP-2之间的复杂相互作用，并确定参与这种相互作用和功能的互补结合位点。(3)研究a1(IV)NC1对a1-整合素零和a1(IV)NC1转基因小鼠肿瘤生长的抑制作用。上述特定目标将通过细胞培养、a1整合素缺失、a1(IV)NC1转基因小鼠和携带a1(IV)NC1结构域表达磁带的腺病毒来实现。我们将使用免疫印迹、共免疫沉淀、免疫组织化学、Matrigel塞和肿瘤研究分析这些模型。这项工作的成功完成将为新的抗血管生成肿瘤疗法的发展提供有价值的见解。