The Novel Mechanisms of Thrombosis Formation in Myeloproliferative Diseases

骨髓增生性疾病血栓形成的新机制

基本信息

  • 批准号:
    10627990
  • 负责人:
  • 金额:
    $ 61.89万
  • 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:
    2020-07-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

Myeloproliferative neoplasms (MPNs) are pro-thrombotic malignancies resulting from the clonal expansion of myeloid cells. MPN patients have a hazard ratio for developing an arterial thrombosis that is similar to cigarette smokers and their risk of developing a venous thrombosis is comparable to Factor V Leiden heterozygotes. Over 100,000 Americans have a myeloproliferative disorder due to JAK2V617F, an activating mutation of JAK2 tyrosine kinase. In addition, the JAK2V617F mutation is a driver of clonal hematopoiesis that may be present in up to 3% of the general population. Even when patients only have clonal hematopoiesis with normal blood counts, the JAK2V617F mutation still confers a 12-fold increased risk for developing a myocardial infarction at an early age. Although notable advances have been made in our understanding of the dysregulation of hematopoiesis in patients with JAK2V617F driven myeloproliferative diseases, remarkably little is known about the molecular basis for why patients with the JAK2V617F mutation are at such high risk for thrombosis. We have found that mice and humans with the JAK2V617F mutation form thrombi that are structurally and mechanically distinct from normal controls. Specifically, our preliminary data shows that the JAK2V617F mutation induces larger clots due to the inability of these clots to compact (i.e. retract) well. Additionally, these clots fail to stabilize because they cannot cover their surface with fibrin, making the clots more friable. Because these clots are larger in size, this makes them more likely to occlude blood flow within blood vessels, and the friable structure of these clots also makes them more likely to embolize. We have also observed that the loss of the phosphoinositide adaptor protein, Pleckstrin-2 (Plek2), or its widely expressed paralog Pleckstrin-1 (Plek1), impair phosphatidylinositol 3-kinase (PI3K) signaling, and thereby reverses many of the widespread vascular occlusions and lethality of JAK2V617F knockin mice. Based on these studies, we hypothesize that both Pleckstrin isoforms are critical for thrombus formation in JAK2V617F driven diseases through phosphoinositide-mediated pathways. The goals of this Proposal are to: (1) achieve a mechanistic understanding of how JAK2-drives thrombosis in MPN disorders, and (2) determine how Plek1 and Plek2 mediate the development of JAK2V617F associated thrombi. A better understanding of the molecular basis for why patients develop thrombosis should have far reaching impact on both understanding and treating patients with JAK2V617F driven diseases.
骨髓增生性肿瘤(MPN)是由骨髓增生异常综合征引起的促血栓形成恶性肿瘤。 骨髓细胞的克隆性扩增。MPN患者有一个风险比, 与吸烟者相似的动脉血栓形成,以及他们发展为 静脉血栓形成与凝血因子V莱顿杂合子相当。超过10万 美国人患有JAK 2 V617 F引起的骨髓增生性疾病,JAK 2 V617 F是一种激活突变, JAK 2酪氨酸激酶。此外,JAK 2 V617 F突变是克隆性表达的驱动因素。 造血系统,可能存在于高达3%的一般人群。即使 患者仅具有血细胞计数正常的克隆性造血,JAK 2 V617 F突变 仍然会增加12倍的早期心肌梗死的风险。 尽管我们对神经系统的失调的理解已经取得了显著的进展, 在JAK 2 V617 F驱动的骨髓增生性疾病患者中, 关于JAK 2 V617 F突变患者为什么会出现这种情况的分子基础知之甚少。 血栓形成的高风险我们发现,携带JAK 2 V617 F的小鼠和人类 突变形成血栓,其在结构和机械上不同于正常对照。 具体地说,我们的初步数据显示JAK 2 V617 F突变诱导更大的凝块, 这是由于这些凝块不能很好地压缩(即收缩)。此外,这些凝块 因为它们不能用纤维蛋白覆盖它们的表面, 易碎因为这些血栓的体积较大,这使得它们更容易闭塞 血液在血管内流动,这些凝块的脆弱结构也使它们 更容易栓塞我们还观察到磷酸肌醇的丢失 衔接蛋白,Pleckstrin-2(Plek 2),或其广泛表达的副产物Pleckstrin-1(Plek 1), 损害磷脂酰肌醇3-激酶(PI 3 K)信号传导,从而逆转许多 广泛的血管闭塞和JAK 2 V617 F基因敲入小鼠的致死性。基于这些 研究中,我们假设这两种Pleckstrin亚型对血栓形成至关重要, 在JAK 2 V617 F通过磷酸肌醇介导的途径驱动的疾病中。的目标 这个建议是:(1)实现JAK 2驱动器的机械理解 MPN疾病中的血栓形成,以及(2)确定Plek 1和Plek 2如何介导MPN疾病中的血栓形成。 JAK 2 V617 F相关血栓的发展。更好地理解分子 为什么患者发生血栓形成的基础应该对两者都有深远的影响 了解和治疗JAK 2 V617 F驱动的疾病患者。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Chorography of blood proteins.
血液蛋白质分布图。
Megakaryocyte-induced contraction of plasma clots: Cellular mechanisms and structural mechanobiology.
  • DOI:
    10.1182/blood.2023021545
  • 发表时间:
    2023-11
  • 期刊:
  • 影响因子:
    20.3
  • 作者:
    Oleg V Kim;R. Litvinov;Alyssa L. Gagne;Deborah L French;Lawrence F. Brass;J. Weisel
  • 通讯作者:
    Oleg V Kim;R. Litvinov;Alyssa L. Gagne;Deborah L French;Lawrence F. Brass;J. Weisel
Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial.
  • DOI:
    10.1038/s41591-021-01538-9
  • 发表时间:
    2021-12
  • 期刊:
  • 影响因子:
    82.9
  • 作者:
    DeAngelo DJ;Radia DH;George TI;Robinson WA;Quiery AT;Drummond MW;Bose P;Hexner EO;Winton EF;Horny HP;Tugnait M;Schmidt-Kittler O;Evans EK;Lin HM;Mar BG;Verstovsek S;Deininger MW;Gotlib J
  • 通讯作者:
    Gotlib J
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CHARLES S. ABRAMS其他文献

CHARLES S. ABRAMS的其他文献

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{{ truncateString('CHARLES S. ABRAMS', 18)}}的其他基金

The Novel Mechanisms of Thrombosis Formation in Myeloproliferative Diseases
骨髓增生性疾病血栓形成的新机制
  • 批准号:
    10424485
  • 财政年份:
    2020
  • 资助金额:
    $ 61.89万
  • 项目类别:
The Novel Mechanisms of Thrombosis Formation in Myeloproliferative Diseases
骨髓增生性疾病血栓形成的新机制
  • 批准号:
    10187644
  • 财政年份:
    2020
  • 资助金额:
    $ 61.89万
  • 项目类别:
Novel Roles for Phosphoinositide Signaling in alpha-Granule Biogenesis
磷酸肌醇信号传导在 α 颗粒生物发生中的新作用
  • 批准号:
    9884351
  • 财政年份:
    2020
  • 资助金额:
    $ 61.89万
  • 项目类别:
Novel Roles for Phosphoinositide Signaling in alpha-Granule Biogenesis
磷酸肌醇信号传导在 α 颗粒生物发生中的新作用
  • 批准号:
    10656287
  • 财政年份:
    2020
  • 资助金额:
    $ 61.89万
  • 项目类别:
Novel Roles for Phosphoinositide Signaling in alpha-Granule Biogenesis
磷酸肌醇信号传导在 α 颗粒生物发生中的新作用
  • 批准号:
    10161821
  • 财政年份:
    2020
  • 资助金额:
    $ 61.89万
  • 项目类别:
Novel Roles for Phosphoinositide Signaling in alpha-Granule Biogenesis
磷酸肌醇信号传导在 α 颗粒生物发生中的新作用
  • 批准号:
    10434809
  • 财政年份:
    2020
  • 资助金额:
    $ 61.89万
  • 项目类别:
Platelet signals and their interface with the external environment
血小板信号及其与外部环境的接口
  • 批准号:
    8909166
  • 财政年份:
    2014
  • 资助金额:
    $ 61.89万
  • 项目类别:
Platelet signals and their interface with the external environment
血小板信号及其与外部环境的接口
  • 批准号:
    8742306
  • 财政年份:
    2014
  • 资助金额:
    $ 61.89万
  • 项目类别:
Platelet signals and their interface with the external environment
血小板信号及其与外部环境的接口
  • 批准号:
    9315871
  • 财政年份:
    2014
  • 资助金额:
    $ 61.89万
  • 项目类别:
The Biological Roles of Phoshadylinositol Transfer Proteins in Platelets
血小板中磷脂肌醇转移蛋白的生物学作用
  • 批准号:
    8257824
  • 财政年份:
    2012
  • 资助金额:
    $ 61.89万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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