12-HETrE regulation of blood coagulation, hemostasis, and thrombosis

12-HETrE 对凝血、止血和血栓形成的调节

基本信息

项目摘要

ABSTRACT Platelets play an essential role in the vessel, maintaining hemostasis and normal blood flow following vascular insult or injury under physiological conditions. While activation of the platelet is essential for adhesion and aggregation to occur at the site of vascular injury, excessive platelet reactivity can lead to the formation of occlusive thrombi, the predominant underlying cause of myocardial infarction and stroke. Current anti-platelet treatments have significantly limited morbidity and mortality due to thrombosis, however they often result in an increased risk of bleeding resulting in a need for novel targets to further decrease platelet reactivity while exhibiting a limited increased risk for bleeding. Our lab and others have provided compelling evidence supporting 12-lipoxygenase (12-LOX), an enzyme highly expressed in the platelet whose primary function is thought to be to produce bioactive oxidized lipids (oxylipins) from the fatty acids embedded in the platelet membrane, as playing an important role in the regulation of platelet activation. The role of newly studied fatty acids in the platelet such as DGLA, DHA, and EPA has yielded strong preliminary data supporting fatty acids and their 12-LOX oxylipins as being important for regulation of platelet function through GPCR and non-GPCR mechanisms. Our lab has identified the first 12-LOX negative regulation pathway in the platelet whereby formation of 12(S)-HETrE induces activation of a Gs-coupled GPCR pathway and activation of PKA resulting in inhibition of platelet activation and clot formation in vivo while not causing an observed increase in bleeding. We propose to investigate the underlying mechanisms by which these 12-LOX oxylipins regulate platelet activity, clotting, and thrombosis while only minimally affecting bleeding. Therefore, we will assess how DGLA and its oxylipin 12(S)-HETrE alters the phospho-proteome through activation of PKA, elucidate the mechanism by which DHA and EPA regulate platelet function and clotting both ex vivo and in vivo through their 12-LOX oxylipins while sparing hemostasis, and assess the mechanism by which the DHA 12- LOX oxylipin 14-HpDHA can be oxidized to form a new class of maresins, Mar1-D3, in order to regulate thrombolysis and clot resolution. Preliminary data suggests the platelet may produce a novel pool for this pro- resolving oxylipins that could play an important role in the underlying mechanism of clot resolution in vivo. Successful completion of this study will for the first time define the mechanism by which 12-LOX oxylipins regulate platelet reactivity in order to both prevent clot formation and resolve pre-existing clots. Understanding these complex signaling pathways represents a seminal advancement in our understanding of how oxylipins like 12(S)-HETrE regulate the blood and will enable for identification of new targets on the platelet for development of the next generation of anti-platelet therapeutics with the added benefit of limited bleeding.
摘要 血小板在血管中起着至关重要的作用,维持止血和血管后的正常血流。 在生理条件下的侮辱或伤害。而血小板的激活对粘附性和 聚集发生在血管损伤部位,过度的血小板反应可导致 闭塞血栓,心肌梗死和中风的主要潜在原因。当前的抗血小板药物 治疗显著降低了血栓形成的发病率和死亡率,但它们通常会导致 出血风险的增加导致需要新的靶点来进一步降低血小板的反应性 表现出有限的增加出血的风险。我们的实验室和其他实验室提供了令人信服的证据 支持12-脂氧合酶(12-LOX),这是一种在血小板中高表达的酶,其主要功能是 被认为是从嵌入在血小板中的脂肪酸中产生生物活性的氧化脂(氧化脂质) 膜在调节血小板活化中起着重要作用。新近研究的肥胖症的作用 血小板中的酸,如DGLA,DHA和EPA,已经产生了支持脂肪酸的强有力的初步数据 其12-LOX氧脂通过GPCR型和非GPCR型对调节血小板功能起重要作用 机制。我们的实验室已经在血小板中发现了第一个12-LOX负性调节途径, 12(S)-HETrE的形成诱导Gs偶联GPCR途径的激活和PKA的激活 抑制体内的血小板活化和凝块形成,同时不引起观察到的出血增加。 我们建议研究这些12-LOX加氧脂调节的潜在机制 血小板活性、凝血和血栓形成,而对出血的影响很小。因此,我们将 评估DGLA及其氧合脂质12(S)-HETrE如何通过激活PKA改变磷酸化蛋白质组, 阐明DHA和EPA在体内外调节血小板功能和凝血功能的机制 通过他们的12-LOX氧脂,同时避免止血,并评估DHA 12- 氧氧脂蛋白14-HpDHA可以被氧化形成一类新的树脂,MaR1-D3,以调节 溶栓和血栓溶解。初步数据表明,血小板可能会为这种亲和力产生一个新的池。 分解氧脂,这可能在体内血栓分解的潜在机制中发挥重要作用。 这项研究的成功完成将首次确定12-LOX氧化脂质的机制 调节血小板的反应性,既能防止血栓形成,又能化解原有的血栓。理解 这些复杂的信号通路代表了我们对氧化脂质如何 如12(S)-HETRE调节血液,并将使识别血小板上的新靶点 开发下一代抗血小板治疗药物,并增加有限出血的好处。

项目成果

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MICHAEL Allan HOLINSTAT其他文献

MICHAEL Allan HOLINSTAT的其他文献

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{{ truncateString('MICHAEL Allan HOLINSTAT', 18)}}的其他基金

2022 Midwest Platelet Conference
2022年中西部血小板会议
  • 批准号:
    10536072
  • 财政年份:
    2022
  • 资助金额:
    $ 39万
  • 项目类别:
Biomarkers for 12-lipoxygenase inhibition as a therapeutic intervention for heparin-induced thrombocytopenia and thrombosis (HIT/T)
12-脂氧合酶抑制的生物标志物作为肝素诱导的血小板减少症和血栓形成的治疗干预措施 (HIT/T)
  • 批准号:
    10427382
  • 财政年份:
    2021
  • 资助金额:
    $ 39万
  • 项目类别:
Biomarkers for 12-lipoxygenase inhibition as a therapeutic intervention for heparin-induced thrombocytopenia and thrombosis (HIT/T)
12-脂氧合酶抑制的生物标志物作为肝素诱导的血小板减少症和血栓形成的治疗干预措施 (HIT/T)
  • 批准号:
    10177358
  • 财政年份:
    2021
  • 资助金额:
    $ 39万
  • 项目类别:
12-HETrE regulation of blood coagulation, hemostasis, and thrombosis
12-HETrE 对凝血、止血和血栓形成的调节
  • 批准号:
    10590459
  • 财政年份:
    2019
  • 资助金额:
    $ 39万
  • 项目类别:
12-HETrE regulation of blood coagulation, hemostasis, and thrombosis
12-HETrE 对凝血、止血和血栓形成的调节
  • 批准号:
    10728385
  • 财政年份:
    2019
  • 资助金额:
    $ 39万
  • 项目类别:
12-HETrE regulation of blood coagulation, hemostasis, and thrombosis
12-HETrE 对凝血、止血和血栓形成的调节
  • 批准号:
    9902471
  • 财政年份:
    2019
  • 资助金额:
    $ 39万
  • 项目类别:
12-HETrE regulation of blood coagulation, hemostasis, and thrombosis
12-HETrE 对凝血、止血和血栓形成的调节
  • 批准号:
    10372074
  • 财政年份:
    2019
  • 资助金额:
    $ 39万
  • 项目类别:
12-HETrE regulation of blood coagulation, hemostasis, and thrombosis
12-HETrE 对凝血、止血和血栓形成的调节
  • 批准号:
    10319403
  • 财政年份:
    2019
  • 资助金额:
    $ 39万
  • 项目类别:
12-HETrE regulation of blood coagulation, hemostasis, and thrombosis
12-HETrE 对凝血、止血和血栓形成的调节
  • 批准号:
    10474068
  • 财政年份:
    2019
  • 资助金额:
    $ 39万
  • 项目类别:
NRSA Training Core
NRSA 培训核心
  • 批准号:
    10116518
  • 财政年份:
    2017
  • 资助金额:
    $ 39万
  • 项目类别:

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