Mechanisms in Blood Clotting

血液凝固机制

• 批准号: 10594476
• 负责人: James H. Morrissey
• 金额: $ 67.73万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-31 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10594476
• 关键词: Area; Arteries; Basic Science; Blood; Blood Coagulation Disorders; Blood coagulation; Coagulation Process; Collagen; Complex; Deep Vein Thrombosis; Disease; Factor VIIa; Goals; Hemophilia A; Hemostatic Agents; Hemostatic function; Human; Inflammation; Laboratories; Life; Molecular; Myocardial Infarction; Nucleic Acids; Pattern; Phospholipids; Polymers; Polyphosphates; Public Health; Reaction; Research; Stroke; System; Thromboplastin; Thrombosis; Veins; Vision; Work; immunothrombosis; insight; pathogen; success; therapeutic target; vascular injury

Abstract The overall vision is to create a detailed understanding of mechanisms that regulate the blood clotting system, with a goal of elucidating the aspects of the clotting machinery that function differentially in hemostasis versus thrombosis. The conceptual framework is that human thrombotic diseases result from an otherwise protective mechanism (immunothrombosis) gone awry. In this view, hemostasis following vascular injury is driven by the prompt exposure of blood to preexisting, natural procoagulants such as tissue factor and collagen that are ubiquitous throughout the body and that induce rapid formation of hemostatic plugs. On the other hand, immunothrombosis is likely triggered and/or greatly enhanced by the elaboration of damage-associated molecular patterns (DAMPs) and pathogen-associate molecular patterns (PAMPs). An important concept is that many of these PAMPs and DAMPs that drive immunothrombosis are potential therapeutic targets that should have little or no involvement in normal hemostasis. In order to achieve this vision, we need to have a much better mechanistic understanding of what regulates blood clotting reactions, and in particular we need to identify and understand the DAMPs that drive thrombosis and coagulopathies. The proposed work will focus on three general areas within this general conceptual framework: elucidating mechanisms by which procoagulant anionic polymers such as polyphosphate (polyP) and nucleic acids trigger regulate blood clotting and inflammation; identifying key structural details that control the function of the tissue factor/factor VIIa complex; and achieving a detailed understanding of how phospholipid bilayers regulate blood clotting reactions. These studies will build on our prior success in this area and will advance the field.

抽象的 总体愿景是对调节血液凝结系统的机制有详细的理解， 以阐明在止血和止血与凝血机制的各个方面的目标 血栓形成。概念框架是人类血栓性疾病是由原本保护性引起的 机制（免疫骨骼）出了问题。从这种角度来看，血管损伤后的止血是由 迅速将血液暴露于先前存在的天然proc仪，例如组织因子和胶原蛋白 无处不在的整个身体，并引起止血塞的快速形成。另一方面， 通过损害相关的阐述，可能会触发和/或大大增强免疫骨栓塞 分子模式（湿）和病原体共同关联的分子模式（PAMPS）。一个重要的概念是 这些驱动免疫栓塞的大型疾病和潮湿是潜在的治疗靶标的 应该很少或根本没有参与正常止血。为了实现这一愿景，我们需要有一个 更好地理解调节血液凝结反应的方法，特别是我们需要 识别并理解驱动血栓形成和凝血病的潮湿。拟议的工作将重点放在 这个一般概念框架中的三个一般领域：阐明procogulant的机制 阴离子聚合物（例如聚磷酸盐（息肉）和核酸触发）调节血液凝结和 炎;确定控制组织因子/因子VIIA复合物功能的关键结构细节； 并详细了解磷脂双层如何调节血液凝结反应。这些 研究将以我们在这一领域的成功为基础，并将推进这一领域。

项目成果

Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies.

酶促氧化的磷脂可恢复凝血因子缺乏时的凝血酶生成。

• DOI: 10.1172/jci.insight.98459
• 发表时间: 2018
• 期刊: JCI insight
• 影响因子: 8
• 作者: Slatter,DavidA;Percy,CharlesL;Allen-Redpath,Keith;Gajsiewicz,JoshuaM;Brooks,NickJ;Clayton,Aled;Tyrrell,VictoriaJ;Rosas,Marcela;Lauder,SarahN;Watson,Andrew;Dul,Maria;Garcia-Diaz,Yoel;Aldrovandi,Maceler;Heurich,Meike;Hall,
• 通讯作者: Hall,

Influence of Steric Shield on Biocompatibility and Antithrombotic Activity of Dendritic Polyphosphate Inhibitor.

• DOI: 10.1021/acs.molpharmaceut.1c00934
• 发表时间: 2022-06-06
• 期刊: MOLECULAR PHARMACEUTICS
• 影响因子: 4.9
• 作者: Abbina, Srinivas;La, Chanel C.;Vappala, Sreeparna;Kalathottukaren, Manu Thomas;Abbasi, Usama;Gill, Arshdeep;Smith, Stephanie A.;Haynes, Charles A.;Morrissey, James H.;Kizhakkedathu, Jayachandran N.
• 通讯作者: Kizhakkedathu, Jayachandran N.

Coagulation factor VIIa binds to herpes simplex virus 1-encoded glycoprotein C forming a factor X-enhanced tenase complex oriented on membranes.

• DOI: 10.1111/jth.14790
• 发表时间: 2020-06
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: Lin BH;Sutherland MR;Rosell FI;Morrissey JH;Pryzdial ELG
• 通讯作者: Pryzdial ELG

Smart thrombosis inhibitors without bleeding side effects via charge tunable ligand design.

• DOI: 10.1038/s41467-023-37709-0
• 发表时间: 2023-04-26
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: La, Chanel C.;Smith, Stephanie A.;Vappala, Sreeparna;Adili, Reheman;Luke, Catherine E.;Abbina, Srinivas;Luo, Haiming D.;Chafeeva, Irina;Drayton, Matthew;Creagh, Louise A. A.;de Guadalupe Jaraquemada-Pelaez, Maria;Rhoads, Nicole;Kalathottukaren, Manu Thomas;Henke, Peter K.;Straus, Suzana K.;Du, Caigan;Conway, Edward M.;Holinstat, Michael;Haynes, Charles A.;Morrissey, James H.;Kizhakkedathu, Jayachandran N.
• 通讯作者: Kizhakkedathu, Jayachandran N.

DNA ladders can be used to size polyphosphate resolved by polyacrylamide gel electrophoresis.

DNA 梯子可用于通过聚丙烯酰胺凝胶电泳来确定聚磷酸盐的大小。

• DOI: 10.1002/elps.201800227
• 发表时间: 2018
• 期刊: Electrophoresis
• 影响因子: 2.9
• 作者: Smith,StephanieA;Wang,Yan;Morrissey,JamesH
• 通讯作者: Morrissey,JamesH