CD39-carrying extracellular vesicles regulate pulmonary thrombosis in Sickle Cell Disease

携带CD39的细胞外囊泡调节镰状细胞病中的肺血栓形成

基本信息

  • 批准号:
    10736531
  • 负责人:
  • 金额:
    $ 78.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-01 至 2027-07-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Sickle cell disease (SCD) is the most common hemolytic disorder affecting African Americans. In situ (de novo) acute pulmonary thrombosis is the underlying cause in ~20% of SCD patients hospitalized with respiratory failure. The current therapy for pulmonary thrombosis in SCD is primarily supportive and a preventive therapy does not exist. Autopsy and computed tomography studies have identified that occlusion of pulmonary arterioles by platelet-rich thrombi contributes to the development of pulmonary thrombosis in SCD patients. Adenosine diphosphate (ADP) released from lysed erythrocytes activates platelets by stimulating purinergic P2Y1 and P2Y12 receptors. We recently discovered that this pathway promotes pulmonary arteriole thrombosis following acute-hemolysis in wild-type mice, suggesting that ADP-induced purinergic signaling may also promote pulmonary thrombosis in a hemolytic disorder such as SCD. However, P2Y12 receptor antagonists have shown no benefit to SCD patients in recent clinical trials, and it remains to be identified why pulmonary thrombosis develops only in a sub-set but not all SCD patients. Identifying molecular and genetic mechanisms that trigger pulmonary thrombosis in SCD, would enable the development of Precision Medicine diagnostic and therapeutic approaches for these at-risk SCD patients. Based on our new preliminary findings, we hypothesize that CD39 (ecto-nucleotidase) present in circulating extracellular vesicles (CD39+-EVs) degrades excess ADP to prevent pulmonary thrombosis in SCD, however, single-nucleotide-polymorphism (SNP) rs3176891G in the CD39- encoding gene (ENTPD1) attenuates this protection and identifies SCD patients who can benefit from anti- purinergic therapy. We will test this hypothesis using our newly developed mouse model of pulmonary thrombosis triggered by intravenous (IV) administration of ADP, in vivo imaging of lung in live mice, in vitro microfluidic studies with SCD patient blood, isolation and characterization of EVs, SCD mice genetically deficient in CD39, and genetic analyses in SCD patients with vs without SNP rs3176891G. In Aim 1, we will determine whether ADP-induced platelet aggregation and pulmonary thrombosis is impaired in SCD. In Aim 2, we will determine whether circulating CD39+-EVs degrade excess ADP to prevent pulmonary thrombosis in SCD. In Aim 3, we will determine whether SNP rs3176891G promotes pulmonary thrombosis event in SCD patients by attenuating CD39+-EVs, leading to increased ADP-induced platelet aggregation. These studies will introduce a novel paradigm that CD39+-EVs prevent pulmonary thrombosis in SCD, and establish the premise for first-ever precision medicine in SCD by identifying rs3176891G as a risk for pulmonary thrombosis.
项目摘要 镰状细胞病(SCD)是影响非洲裔美国人的最常见的溶血性疾病。原位(重新) 急性肺血栓形成是约20%的SCD患者因呼吸系统疾病住院的根本原因。 失败目前对SCD肺血栓形成的治疗主要是支持性和预防性治疗 不存在.尸检和计算机断层扫描研究表明,肺小动脉闭塞 富含血小板的血栓导致SCD患者肺血栓形成。腺苷 从溶解的红细胞释放的二磷酸盐(ADP)通过刺激嘌呤能P2 Y1和 P2 Y12受体。我们最近发现,这一途径促进肺小动脉血栓形成, 野生型小鼠的急性溶血,表明ADP诱导的嘌呤能信号也可能促进 溶血性疾病如SCD中的肺血栓形成。然而,P2 Y12受体拮抗剂已经显示, 在最近的临床试验中,SCD患者没有获益,肺血栓形成的原因仍有待确定。 仅在一个子集中发生,而不是所有SCD患者。识别触发的分子和遗传机制 SCD中的肺血栓形成,将使精确医学诊断和治疗的发展 为这些高危SCD患者提供治疗方法。基于我们新的初步发现,我们假设CD 39 存在于循环细胞外囊泡(CD 39 +-EV)中的外核苷酸酶(外核苷酸酶)降解过量的ADP,以防止 然而,SCD中的肺血栓形成,CD 39-T细胞中的单核苷酸多态性(SNP)rs3176891 G, 编码基因(ENTPD 1)减弱了这种保护作用,并确定了SCD患者谁可以受益于抗- 嘌呤能疗法我们将使用我们新开发的小鼠肺模型来验证这一假设。 静脉内(IV)给予ADP引发血栓形成,活小鼠肺的体内成像,体外 SCD患者血液的微流控研究,EV的分离和表征,遗传缺陷的SCD小鼠 在CD 39中,以及在具有与不具有SNP rs3176891 G的SCD患者中的遗传分析。在目标1中,我们将确定 ADP诱导的血小板聚集和肺血栓形成是否在SCD中受损。在目标2中,我们将 确定循环CD 39 +-EV是否降解过量ADP以预防SCD中的肺血栓形成。在Aim中 3、我们将确定SNP rs3176891 G是否促进SCD患者的肺血栓形成事件, 减弱CD 39 +-EV,导致ADP诱导的血小板聚集增加。这些研究将介绍一个 CD 39 +-EV预防SCD肺血栓形成的新范式,并为首次 通过将rs3176891 G确定为肺血栓形成的风险,在SCD中进行精准医学。

项目成果

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Prithu Sundd其他文献

Prithu Sundd的其他文献

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{{ truncateString('Prithu Sundd', 18)}}的其他基金

Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome
急性胸部综合征中血小板-中性粒细胞微栓塞引起的肺动脉闭塞
  • 批准号:
    9273634
  • 财政年份:
    2015
  • 资助金额:
    $ 78.95万
  • 项目类别:
Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome
急性胸部综合征中血小板-中性粒细胞微栓塞引起的肺动脉闭塞
  • 批准号:
    10625962
  • 财政年份:
    2015
  • 资助金额:
    $ 78.95万
  • 项目类别:
Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome
急性胸部综合征中血小板-中性粒细胞微栓塞引起的肺动脉闭塞
  • 批准号:
    10205691
  • 财政年份:
    2015
  • 资助金额:
    $ 78.95万
  • 项目类别:
Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome
急性胸部综合征中血小板-中性粒细胞微栓塞引起的肺动脉闭塞
  • 批准号:
    8939237
  • 财政年份:
    2015
  • 资助金额:
    $ 78.95万
  • 项目类别:
Pulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest Syndrome
急性胸部综合征中血小板-中性粒细胞微栓塞引起的肺动脉闭塞
  • 批准号:
    10390355
  • 财政年份:
    2015
  • 资助金额:
    $ 78.95万
  • 项目类别:

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