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: 8357281
• 负责人: YOSHIKAZU TAKADA
• 金额: $ 2.52万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357281
• 关键词: Affect; Angiogenesis Inhibitors; Anti-Inflammatory Agents; Apoptosis; Asthma; Binding; Binding Sites; Blood Platelets; C-terminal; California; Cell Adhesion; Chronic; Disease; Endothelial Cells; Experimental Autoimmune Encephalomyelitis; Fibrin; Fibrinogen; Funding; Grant; In Vitro; Inflammation; Inflammatory; Integrins; Leukocytes; Modeling; Multiple Sclerosis; Mus; National Center for Research Resources; Pharmacia brand of estropipate; Play; Primates; Principal Investigator; Process; Publishing; Research; Research Infrastructure; Resources; Role; Signal Transduction; Source; Symptoms; Testing; United States National Institutes of Health; Xenograft Model; adhesion receptor; angiogenesis; cancer cell; cell injury; cell type; cost; 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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 纤维蛋白原诱导增殖信号，但它的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）的信号转导中起关键作用。纤维蛋白原γ链具有C末端球状结构域（γ C，γ链的残基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α v β 3和白细胞α M β 2）结合。我们发现，分离的γ C片段及其截短突变体（γ C399 TR，12残基截短）诱导内皮细胞在体外凋亡，而天然纤维蛋白原或片段D没有。γ C或γ C399 tr不影响所测试的几种其它细胞类型（包括角质形成细胞和癌细胞）的增殖。我们发现α v β 3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γ C和γ C399 tr中暴露。这些结果表明，γ C和γ C399 tr是潜在的抗血管生成剂，γ C和γ C399 tr中的决定簇（其在纤维蛋白原和片段D中是隐蔽的）参与内皮细胞凋亡，并且整合素潜在地参与该过程。我们还表明，γ C399 tr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γ C399 tr降低了荷瘤小鼠中循环内皮细胞（CEC）（血管生成的标志物）的水平（我们未发表的结果），我们假设这是γ C399 tr抗血管生成作用的潜在机制。最近已经认识到血管生成在慢性炎症中起作用。我们最近发现，γ C399 tr显着抑制实验性过敏性脑脊髓炎（EAE），多发性硬化症（MS）样疾病的小鼠（我们未发表的结果）的发病。我们假设γ C399 tr也可能具有作为抗炎剂的潜力，并抑制灵长类动物中的血管生成和慢性炎症。 我们建议在灵长类动物炎症模型中测试γ C399 tr是否可能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动物哮喘模型。我们预期γ C399 tr将显示抗血管生成和炎症作用，从而改善该模型中的哮喘症状。