POTENTIAL OF NOVEL ANTI-INFLAMMATORY AGENTS TO SUPPRESS CHRONIC INFLAMMATION

新型抗炎药抑制慢性炎症的潜力

• 批准号: 8172556
• 负责人: YOSHIKAZU TAKADA
• 金额: $ 3.8万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172556
• 关键词: Affect; Angiogenesis Inhibitors; Anti-Inflammatory Agents; Apoptosis; Asthma; Binding; Binding Sites; Blood Platelets; C-terminal; Cell Adhesion; Chronic; Computer Retrieval of Information on Scientific Projects Database; Disease; Endothelial Cells; Experimental Autoimmune Encephalomyelitis; Fibrin; Fibrinogen; Funding; Grant; In Vitro; Inflammation; Inflammatory; Institution; Integrins; Leukocytes; Modeling; Multiple Sclerosis; Mus; Pharmacia brand of estropipate; Play; Primates; Process; Publishing; Research; Research Personnel; Resources; Role; Signal Transduction; Source; Symptoms; Testing; United States National Institutes of Health; Xenograft Model; adhesion receptor; angiogenesis; cancer cell; cell injury; cell type; fibrinogen D fragment; fibrinopeptides gamma; improved; keratinocyte; mutant; novel; tumor; tumor growth; tumor xenograft

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Fibrin(ogen) induces proliferative signals, but some of its proteolytic fragments induce endothelial cell injury. Integrins are known to play a critical role in signal transduction from fibrin(ogen). The fibrinogen gamma chain has a C-terminal globular domain (gamma C, residues 151-411 of gamma chain, 30 Kd) to which several integrin cell adhesion receptors (e.g., platelet alpha IIb beta 3, endothelial alpha v beta 3, and leukocyte alpha M beta 2) bind. We found that the isolated gamma C fragment and its truncation mutant (gamma C399tr, 12 residue truncation) induced apoptosis of endothelial cells in vitro, while native fibrinogen or fragment D did not. gamma C or gamma C399tr did not affect proliferation of several other cell types tested including keratinocytes and cancer cells. We found that the binding site for alpha v beta 3 is cryptic in native fibrinogen and proteolytic fragment D, but is exposed in gamma C and gamma C399tr. These results suggest that gamma C and gamma C399tr are potential anti-angiogenic agents, that determinants in gamma C and gamma C399tr (which are cryptic in fibrinogen and fragment D) are involved in endothelial cell apoptosis, and that integrins are potentially involved in this process. Also we showed that gamma C399tr suppressed tumor growth in tumor xenograft models. These results were recently published [1]. Furthermore we found that gamma C399tr reduced the level of circulating endothelial cells (CEC), a marker of angiogenesis, in tumor-bearing mice (our unpublished results) and we hypothesize that this is a potential mechanism of anti-angiogenic action by gamma C399tr. It has been recently recognized that angiogenesis plays a role in chronic inflammation. We recently found that gamma C399tr markedly suppressed the onset of experimental allergic encephalomyelitis (EAE), a multiple sclerosis (MS)-like disease in mice (our unpublished results). We hypothesize that gamma C399tr may have potential as an anti-inflammatory agent as well, and suppress angiogenesis and chronic inflammation in primate. We propose to test whether gamma C399tr may have potential as anti-angiogenic and anti-inflammatory agent in primate inflammation models. We will use the well-established primate asthma model for this purpose. We expect that gamma C399tr will show anti-angiogenic and inflammatory effects and thus improve asthma symptoms in this model. We propose to test whether gamma C399tr may have potential as anti-angiogenic and anti-inflammatory agent in primate inflammation models. We will use the well-established primate asthma model for this purpose. We expect that gamma C399tr will show anti-angiogenic and inflammatory effects and thus improve asthma symptoms in this model.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 纤维蛋白（原）诱导增殖信号，但其一些蛋白水解片段诱导内皮细胞损伤。已知整合素在纤维蛋白（原）的信号转导中发挥关键作用。纤维蛋白原 γ 链具有 C 末端球状结构域（γ C，γ 链残基 151-411，30 Kd），几种整联蛋白细胞粘附受体（例如血小板 α IIb β 3、内皮细胞 α v β 3 和白细胞 α M β 2）与其结合。我们发现分离的γC片段及其截短突变体（γC399tr，12个残基截短）在体外诱导内皮细胞凋亡，而天然纤维蛋白原或片段D则不然。 gamma C 或 gamma C399tr 不影响测试的几种其他细胞类型的增殖，包括角质形成细胞和癌细胞。我们发现αvβ3的结合位点在天然纤维蛋白原和蛋白水解片段D中是隐蔽的，但在γC和γC399tr中暴露。这些结果表明，γ C 和γ C399tr 是潜在的抗血管生成剂，γ C 和γ C399tr 中的决定簇（在纤维蛋白原和片段D 中是隐秘的）参与内皮细胞凋亡，并且整联蛋白可能参与该过程。我们还表明，γ C399tr 可抑制肿瘤异种移植模型中的肿瘤生长。这些结果最近发表[1]。此外，我们发现，在荷瘤小鼠中，γ C399tr 降低了循环内皮细胞 (CEC) 的水平，CEC 是血管生成的标志物（我们未发表的结果），我们假设这是γ C399tr 抗血管生成作用的潜在机制。最近人们认识到血管生成在慢性炎症中发挥作用。我们最近发现，γ C399tr 显着抑制实验性过敏性脑脊髓炎 (EAE) 的发作，这是一种小鼠多发性硬化症 (MS) 样疾病（我们未发表的结果）。我们假设 γ C399tr 也可能具有作为抗炎剂的潜力，并抑制灵长类动物的血管生成和慢性炎症。 我们建议在灵长类炎症模型中测试 γ C399tr 是否具有作为抗血管生成和抗炎剂的潜力。为此，我们将使用成熟的灵长类哮喘模型。我们预计 γ C399tr 将表现出抗血管生成和炎症作用，从而改善该模型中的哮喘症状。 我们建议在灵长类炎症模型中测试 γ C399tr 是否具有作为抗血管生成和抗炎剂的潜力。为此，我们将使用成熟的灵长类哮喘模型。我们预计 γ C399tr 将表现出抗血管生成和炎症作用，从而改善该模型中的哮喘症状。