Contribution of Structural Motifs to Heparin Clearance

结构基序对肝素清除的贡献

基本信息

项目摘要

DESCRIPTION (provided by applicant): Heparin is a widely-used and important drug, particularly for the aging US population. It is a carbohydrate-based anticoagulant that used by elderly patients for many applications, including thrombotic disorders, in surgery, and during kidney dialysis. The long-term goal of this project is to create synthetic heparin drugs that are safer, more effective, and better tailored to different applications than the currently-available drugs. Heparin has a highly-variable structure due to the abundance of sulfate groups along its backbone, and its chemical structure determines its biological effect. Heparin is difficult to dose for elderly patients, and has well- documented bleeding side effects and contamination issues. In addition, different heparin applications require different rates of drug clearance; for example, the anticoagulant effect during surgery should be eliminated quickly after administration stops, while in deep vein thrombosis treatment the effect should be prolonged. Although there are several heparin drugs on the market, there is a significant need for heparins with homologous structures and controlled rates of clearance. We propose to determine the effects of different structural motifs on the rate of heparin clearance with the aim of developing structurally-defined heparin analogs with varied cellular internalization and clearance rates. To achieve this goal, we will use a unique chemoenzymatic method to synthesize radioactively-labeled heparin constructs having defined sulfation patterns, sulfation densities and lengths. The internalization rates of these constructs will be tested in an experimental cell line (Flp-In 293 cells), and their binding affinities to the heparin clearance receptor, HARE, will be determined using biochemical assays. The constructs will also be tested in human endothelial cells, which are known to internalize and degrade heparin in vivo. Lastly, we will prepare stable isotopically-labeled constructs having different internalization rates and test their clearance and anticoagulant activity in a mouse model. From these studies, we hope to elucidate the specific carbohydrate structures that control heparin clearance, which will be a powerful tool in creating anticoagulant drugs that are tailored to specific applications and patients. PUBLIC HEALTH RELEVANCE: Heparin is a common anticoagulant used during surgery, kidney dialysis and the treatment of thrombosis. This project aims to elucidate how different heparin structures control the rates at which heparin is cleared from the body, which would allow the creation of heparins that are safer and specifically tailored to different treatments.
描述(由申请人提供):肝素是一种广泛使用的重要药物,特别是对美国老龄化人口。它是一种以碳水化合物为基础的抗凝剂,用于老年患者的许多应用,包括血栓性疾病、手术和肾透析。该项目的长期目标是创造出比现有药物更安全、更有效、更适合不同应用的肝素合成药物。肝素具有高度可变的结构,因为它的主链上有丰富的硫酸盐基团,它的化学结构决定了它的生物效应。肝素对老年患者很难给药,并且有充分的证据表明其有出血的副作用和污染问题。此外,不同的肝素应用需要不同的药物清除率;例如,手术时的抗凝作用应在停药后迅速消除,而在治疗深静脉血栓时则应延长抗凝作用。虽然市场上有几种肝素药物,但对具有同源结构和清除率可控的肝素的需求很大。我们建议确定不同结构基序对肝素清除率的影响,目的是开发具有不同细胞内化和清除率的结构定义的肝素类似物。为了实现这一目标,我们将使用一种独特的化学酶方法来合成放射性标记的肝素结构物,这些肝素结构物具有明确的磺化模式、磺化密度和长度。这些构建体的内化率将在实验细胞系(Flp-In 293细胞)中进行测试,它们与肝素清除受体(HARE)的结合亲和力将通过生化分析来确定。这些结构也将在人内皮细胞中进行测试,已知内皮细胞在体内内化和降解肝素。最后,我们将制备具有不同内化率的稳定同位素标记构建物,并在小鼠模型中测试其清除率和抗凝血活性。从这些研究中,我们希望阐明控制肝素清除的特定碳水化合物结构,这将成为创造针对特定应用和患者的抗凝血药物的有力工具。

项目成果

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Elizabeth Pempe Chappell其他文献

Elizabeth Pempe Chappell的其他文献

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{{ truncateString('Elizabeth Pempe Chappell', 18)}}的其他基金

Contribution of Structural Motifs to Heparin Clearance
结构基序对肝素清除的贡献
  • 批准号:
    8337482
  • 财政年份:
    2011
  • 资助金额:
    $ 2.9万
  • 项目类别:

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