ANTIADHESIVE AND ANTICOAGULANT ACTIVITY OF KININOGENS

激肽原的抗粘连和抗凝血活性

基本信息

  • 批准号:
    6110740
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1999
  • 资助国家:
    美国
  • 起止时间:
    1999-06-01 至 1999-06-30
  • 项目状态:
    已结题

项目摘要

The biochemistry, cell and molecular biology of high (HK) and low (LK) molecular weight kininogens will be studied to learn about structure-function correlates as they relate to binding to and effects on blood and vascular cells. D5 has been identified as the region that interacts with anionic surfaces and as a binding site for HKA to neutrophils. Deletion mutants as well as synthesized peptides should allow mapping of the sequence(s) required for binding to neutrophils and endothelial cells. Physical studies of D5 with and without Zn plus plus will be performed. A 31 amino acid sequence in D6 contains sufficient information to bind to two noncontinuous sites on prekallikrein. Using peptides and deletion mutagenesis of D6, the minimal sequences for binding and the topology of HK binding to prekallikrein will be determined. We use these peptides and cognate peptides of prekallikrein to down-regulate fibrinolysis on endothelial cells. D3 has previously been identified as one cell binding region for platelets, endothelial cells and neutrophils. Exons 7, 8, and 9 coding for D3 will be expressed to test the hypothesis that one of the exon products contains all of the information for neutrophil binding on the heavy chain, while another is responsible for inhibiting the binding of thrombin to platelets and endothelial cells. Synthesized, conformationally restrained peptides will be used for fine mapping based on surface-accessible regions of a molecular model of D3 of HK. HK binds to neutrophils on Mac-1, and we will further map the ligand and receptor to better define the interaction. We have recently shown that fibrinogen does not compete with HK binding to endothelial cells, and an antibody to alpha nu beta 3 does not inhibit HK binding, ruling out alpha nu beta 3 as the receptor for HK. However, we found that vitronectin and soluble urokinase receptor inhibit HK binding, suggesting that the UK receptor is the binding site for HK. We will further test this hypothesis by mapping the HK binding site on the UK receptor and map the binding site on HK to the receptor. The mechanism by which HK blocks thrombin binding to platelets by interaction with the thrombin receptor or GPIb will be explored. Kininogen-deficient rats will be used to verify whether HK or LK is an important anti-thrombotic protein. Peptides from kininogen domains will be tested in rats for their antiadhesive and antiplatelet potential. Such polypeptides could serve as templates for peptidomimetic compounds, which should be therapeutic in sepsis, arthritis, hereditary angioedema, and gingival disease in addition to reocclusion after thrombolytic therapy.
高(HK)和低(HK)的生物化学、细胞和分子生物学 (LK)分子量的激肽原将被研究,以了解 结构-功能相关,因为它们涉及与 血液和血管细胞。 D5已被确定为 与阴离子表面相互作用,并作为HKA的结合位点, 中性粒细胞 缺失突变体以及合成肽应该 允许定位结合嗜中性粒细胞所需的序列 和内皮细胞。 具有和不具有Zn+的D5的物理研究 加将执行。 D 6中的31个氨基酸序列含有 足够的信息绑定到两个不连续的网站上 前激肽释放酶 使用肽和D 6的缺失诱变, 最小序列绑定和HK绑定到 前激肽释放酶将被确定。 我们使用这些肽和同源物 前激肽释放酶肽下调内皮细胞上的纤溶 细胞D3以前已被鉴定为一个细胞结合区, 血小板、内皮细胞和嗜中性粒细胞。 外显子7、8和9编码 将表达D3,以检验外显子之一 产品包含所有的信息,中性粒细胞结合的 重链,而另一个是负责抑制结合 凝血酶对血小板和内皮细胞的作用。 合成的, 构象受限的肽将用于精细作图 基于D3分子模型的表面可及区域, HK. HK与Mac-1上的中性粒细胞结合,我们将进一步绘制 配体和受体,以更好地定义相互作用。 我们最近 显示纤维蛋白原不与HK竞争结合, 内皮细胞,并且α nu β 3的抗体不抑制 HK结合,排除α nu β 3作为HK受体。 然而,我们发现玻连蛋白和可溶性尿激酶受体 抑制HK结合,表明UK受体是结合位点 对于HK。 我们将进一步测试这一假设, 结合位点,并将HK上的结合位点映射到 受体的 HK阻断凝血酶结合的机制 血小板通过与凝血酶受体或GPIb的相互作用, 探讨了 激肽原缺乏的大鼠将用于验证HK LK是一种重要的抗血栓蛋白。 肽 将在大鼠中测试激肽原结构域的抗粘附性, 抗血小板潜能。 这样的多肽可以作为模板, 拟肽化合物,其应该在脓毒症中是治疗性的, 关节炎、遗传性血管性水肿和牙龈疾病, 溶栓治疗后再闭塞。

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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Robert W Colman其他文献

Effect of Anti-P1<sup>A1</sup> Antibody on Human Platelets. II. Mechanism of the Complement-Dependent Release Reaction
  • DOI:
    10.1182/blood.v53.4.578.578
  • 发表时间:
    1979-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Alan D Schreiber;Douglas B Cines;Chester Zmijewski;Robert W Colman
  • 通讯作者:
    Robert W Colman

Robert W Colman的其他文献

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{{ truncateString('Robert W Colman', 18)}}的其他基金

Innate Immunity in Experimental Arthritis of Kininogen
激肽原实验性关节炎的先天免疫
  • 批准号:
    6948560
  • 财政年份:
    2004
  • 资助金额:
    --
  • 项目类别:
Innate Immunity in Experimental Arthritis of Kininogen
激肽原实验性关节炎的先天免疫
  • 批准号:
    7121265
  • 财政年份:
    2004
  • 资助金额:
    --
  • 项目类别:
Innate Immunity in Experimental Arthritis of Kininogen
激肽原实验性关节炎的先天免疫
  • 批准号:
    7020439
  • 财政年份:
    2004
  • 资助金额:
    --
  • 项目类别:
Innate Immunity in Experimental Arthritis of Kininogen
激肽原实验性关节炎的先天免疫
  • 批准号:
    6838311
  • 财政年份:
    2004
  • 资助金额:
    --
  • 项目类别:
Innate Immunity in Experimental Arthritis of Kininogen
激肽原实验性关节炎的先天免疫
  • 批准号:
    7280950
  • 财政年份:
    2004
  • 资助金额:
    --
  • 项目类别:
Active site amino acids of cAMP phosphodiesterase 3A
cAMP磷酸二酯酶3A的活性位点氨基酸
  • 批准号:
    6570526
  • 财政年份:
    2002
  • 资助金额:
    --
  • 项目类别:
Active site amino acids of cAMP phosphodiesterase 3A
cAMP磷酸二酯酶3A的活性位点氨基酸
  • 批准号:
    6587891
  • 财政年份:
    2002
  • 资助金额:
    --
  • 项目类别:
ANTIADHESIVE AND ANTICOAGULANT ACTIVITY OF KININOGENS
激肽原的抗粘连和抗凝血活性
  • 批准号:
    6485294
  • 财政年份:
    2001
  • 资助金额:
    --
  • 项目类别:
Active site amino acids of cAMP phosphodiesterase 3A
cAMP磷酸二酯酶3A的活性位点氨基酸
  • 批准号:
    6448223
  • 财政年份:
    2001
  • 资助金额:
    --
  • 项目类别:
MOLECULAR BASIS FOR PLATELET FUNCTION IN HEMOSTASIS
血小板止血功能的分子基础
  • 批准号:
    6748112
  • 财政年份:
    2000
  • 资助金额:
    --
  • 项目类别:

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