Identification of an inhibitor of PDI-GPIbalpha signaling as a novel antithromboinflammatory agent
鉴定 PDI-GPIbalpha 信号传导抑制剂作为新型抗血栓炎症剂
基本信息
- 批准号:10242945
- 负责人:
- 金额:$ 55.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-04 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimal ModelAnimalsAnti-Inflammatory AgentsAntibodiesAsiaBackBindingBleeding time procedureBlocking AntibodiesBlood PlateletsBlood VesselsBlood flowCanis familiarisCardiovascular DiseasesCessation of lifeChemicalsComputer AssistedDataDevelopmentDiseaseDoseDrug DesignDrug KineticsEndotheliumEuropeExhibitsExtracellular ProteinFutureGlycoproteinsGoalsHemorrhageHemostatic functionImmune responseImpairmentIn VitroInflammationInjectionsIntegrinsInvestigational New Drug ApplicationKnockout MiceLeadLeukocytesLigand BindingLigandsMacrophage-1 AntigenMediatingMegakaryocytesMolecular ConformationMusMyocardial InfarctionNeutrophil InfiltrationPathologicPathologyPatientsPeripheralPharmaceutical PreparationsPlatelet AdhesivenessPlatelet aggregationProtein Disulfide IsomeraseProtein InhibitionRiskSeriesSignal PathwaySignal TransductionSignaling MoleculeSpecificityStrokeSurfaceTailTechniquesTechnologyTertiary Protein StructureTestingTherapeuticThrombosisThrombusTissuesToxic effectVasculitisatherothrombosisconditional knockoutdrug metabolismefficacy studyhigh throughput screeningimprovedin vivoinhibitor/antagonistmouse modelneutrophilnonhuman primatenovelnovel therapeuticsplatelet functionpreclinical studypreventreceptorscaffoldsmall moleculesmall molecule inhibitortargeted treatmenttherapeutically effectivethromboinflammationvascular inflammation
项目摘要
Project Summary
Thromboinflammatory diseases, including atherothrombosis, stroke and peripheral vasculitis, result in >30% of
all deaths globally. Underlying the pathology of thromboinflammation is increased adhesiveness of platelets and
leukocytes. Although many antiplatelet and anti-inflammatory therapies have been used for disease treatment,
these drugs increase the risk of major bleeding or impair immune responses. Using protein disulfide isomerase
(PDI) conditional knockout (CKO) mice and inhibitors, we and others have shown that extracellular PDI is crucial
for platelet thrombus formation in arterial thrombosis and neutrophil recruitment to inflamed endothelium in
vascular inflammation. However, inhibition of extracellular PDI with a function-blocking antibody prolongs tail
bleeding times in mice, raising a concern that specific inhibition of PDI may perturb hemostatic function. Our
recent studies have demonstrated that platelet-released PDI promotes the ligand-binding function of glycoprotein
Ibα (GPIbα) and enhances GPIbα-mediated platelet adhesiveness, platelet-neutrophil aggregation and vascular
occlusion under thromboinflammatory conditions. These results suggest that inhibitors blocking the PDI-GPIbα
signaling axis may be a novel antithromboinflammatory drug. Using high throughput screening, we have
identified one compound that specifically inhibits PDI-GPIbα binding and GPIbα-mediated platelet aggregation.
We have found that iv injection of the compound into mice abolishes platelet-neutrophil interactions and improves
blood flow rates in microvessels under thromboinflammatory conditions. Unlike a conventional inhibitor of PDI or
GPIbα, treatment with our compound does not prolong tail bleeding times in mice. These results have provided
evidence for the feasibility of identifying small-molecule inhibitors targeting a specific PDI signaling pathway. In
Aim 1, using the computer-aided drug design technique and a series of in vitro studies, we will identify small-
molecule compounds that specifically block PDI-GPIbα signaling and GPIbα-mediated platelet functions. In Aim
2, we will synthesize derivatives of hits, test them in animal studies and examine DMPK profiles of the selected
compounds. The proposed study will prove that compared to conventional inhibition of PDI or GPIbα, specific
inhibition of the PDI-GPIbα signaling axis might be a safer and effective therapeutic strategy for treating
thromboinflammatory disease.
项目摘要
血栓炎性疾病,包括动脉粥样硬化、中风和外周血管炎,导致>30%的
全球所有死亡人数。血栓炎症的病理基础是血小板的增殖增加,
白细胞尽管许多抗血小板和抗炎疗法已用于疾病治疗,
这些药物会增加大出血的风险或损害免疫反应。利用蛋白质二硫键异构酶
(PDI)条件性基因敲除(CKO)小鼠和抑制剂,我们和其他人已经表明,细胞外PDI是至关重要的,
对于动脉血栓形成中的血小板血栓形成和
血管炎症然而,用功能阻断抗体短尾抑制细胞外PDI,
出血时间,引起了对PDI的特异性抑制可能扰乱止血功能的担忧。我们
最近的研究表明,血小板释放的PDI促进糖蛋白的配体结合功能
GPIbα可增强GPIbα介导的血小板聚集、血小板-中性粒细胞聚集和血管生成
血栓炎性条件下的闭塞。这些结果表明阻断PDI-GPIbα的抑制剂
信号转导轴可能是一种新的抗血栓炎症药物。使用高通量筛选,我们有
鉴定了一种特异性抑制PDI-GPIbα结合和GPIbα介导的血小板聚集的化合物。
我们已经发现,将该化合物静脉注射到小鼠体内可以消除血小板-中性粒细胞的相互作用,并改善
血栓炎性条件下微血管中的血流速率。与常规的PDI抑制剂或
GPIbα,用我们的化合物治疗不会延长小鼠的尾部出血时间。这些结果提供了
鉴定靶向特定PDI信号通路的小分子抑制剂的可行性的证据。在
目的1、利用计算机辅助药物设计技术和一系列体外研究,筛选小分子药物,
特异性阻断PDI-GPIbα信号传导和GPIbα介导的血小板功能的分子化合物。在Aim中
2,我们将合成命中衍生物,在动物研究中测试它们,并检查所选的DMPK谱。
化合物.本研究将证明,与常规抑制PDI或GPIbα相比,
抑制PDI-GPIbα信号转导轴可能是一种更安全有效的治疗策略,
血栓炎性疾病
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jaehyung Cho其他文献
Jaehyung Cho的其他文献
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{{ truncateString('Jaehyung Cho', 18)}}的其他基金
Targeting LRRC8 signaling to prevent & treat arterial thrombosis in type 2 diabetes
针对 LRRC8 信号传导以防止
- 批准号:
10765748 - 财政年份:2023
- 资助金额:
$ 55.13万 - 项目类别:
ERO1 alpha in platelet activity and thrombosis
ERO1 α 在血小板活性和血栓形成中的作用
- 批准号:
10321687 - 财政年份:2020
- 资助金额:
$ 55.13万 - 项目类别:
Identification of an inhibitor of PDI-GPIbalpha signaling as a novel antithromboinflammatory agent
鉴定 PDI-GPIbalpha 信号传导抑制剂作为新型抗血栓炎症剂
- 批准号:
10253656 - 财政年份:2020
- 资助金额:
$ 55.13万 - 项目类别:
ERO1 alpha in platelet activity and thrombosis
ERO1 α 在血小板活性和血栓形成中的作用
- 批准号:
10285785 - 财政年份:2020
- 资助金额:
$ 55.13万 - 项目类别:
Role of intravascular ERO1@ in acute lung injury
血管内ERO1@在急性肺损伤中的作用
- 批准号:
10686908 - 财政年份:2020
- 资助金额:
$ 55.13万 - 项目类别:
Role of intravascular ERO1@ in acute lung injury
血管内ERO1@在急性肺损伤中的作用
- 批准号:
10267181 - 财政年份:2020
- 资助金额:
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Ero1α in platelet activity and thrombosis
Ero1α 在血小板活性和血栓形成中的作用
- 批准号:
9884277 - 财政年份:2020
- 资助金额:
$ 55.13万 - 项目类别:
Role of intravascular ERO1@ in acute lung injury
血管内ERO1@在急性肺损伤中的作用
- 批准号:
10469645 - 财政年份:2020
- 资助金额:
$ 55.13万 - 项目类别:
Role of intravascular ERO1@ in acute lung injury
血管内ERO1@在急性肺损伤中的作用
- 批准号:
10027023 - 财政年份:2020
- 资助金额:
$ 55.13万 - 项目类别:
ERO1 alpha in platelet activity and thrombosis
ERO1 α 在血小板活性和血栓形成中的作用
- 批准号:
10621694 - 财政年份:2020
- 资助金额:
$ 55.13万 - 项目类别:
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