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
• 负责人: CHARLES S. ABRAMS
• 金额: $ 61.89万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10424485
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adaptor Signaling Protein; Affect; Age; Aging; American; Atherosclerosis; Binding; Biological; Blood; Blood Platelets; Blood Vessels; Blood coagulation; Blood flow; Cells; Cigarette Smoker; Clonal Expansion; Coagulation Process; Collaborations; Data; Development; Diagnosis; Disease; Electron Microscopy; Erythrocytes; Event; Fibrin; General Population; Goals; Hematopoiesis; Heterozygote; Human; Impairment; Individual; Induced Mutation; JAK2 gene; Kinetics; Knock-in Mouse; Label; Lipids; Malignant Neoplasms; Mechanics; Mediating; Modeling; Molecular; Mus; Mutation; Myeloid Cells; Myeloproliferative disease; Myocardial Infarction; Nature; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphatidylinositols; Phosphotransferases; Process; Protein Isoforms; Protein Tyrosine Kinase; Proteins; Prothrombin; Risk; Role; Series; Signal Transduction; Stroke; Structure; Surface; Survival Analysis; Therapeutic Embolization; Thrombosis; Thrombus; Universities; Venous Thrombosis; base; design; experimental study; factor V Leiden; hazard; high risk; human old age (65+); in vivo; knockout gene; new therapeutic target; novel; paralogous gene; platelet protein P47; thrombotic

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)是一种血栓前恶性肿瘤，由 髓系细胞克隆性扩增。MPN患者发生AFP的风险比 类似于吸烟者的动脉血栓形成及其发生 静脉血栓形成类似于因子V Leiden杂合子。超过100,000 美国人患有由JAK2V617F引起的骨髓增殖性疾病，JAK2V617F是一种激活的 JAK2酪氨酸激酶。此外，JAK2V617F突变是克隆的驱动因素 可能存在于高达3%的普通人群中的造血功能。即使是在 患者只有血细胞计数正常的克隆性造血，JAK2V617F突变 仍然会使早年发生心肌梗死的风险增加12倍。 尽管在我们对失调症的理解上取得了显著的进展 JAK2V617F驱动的骨髓增殖性疾病患者的造血功能显著 JAK2V617F突变患者的分子基础还知之甚少 有很高的血栓形成风险。我们发现，携带JAK2V617F的小鼠和人类 突变形成的血栓在结构和机械上都与正常对照组不同。 具体地说，我们的初步数据显示JAK2V617F突变会导致更大的血栓 由于这些凝块不能很好地致密(即回缩)。此外，这些血栓不能 为了稳定，因为它们不能用纤维蛋白覆盖它们的表面，从而使血栓 易碎的。因为这些血栓较大，这使得它们更有可能闭塞。 血管内的血液流动，这些凝块的易碎结构也使它们 更有可能进行栓塞。我们还观察到，肌醇磷脂的损失 接头蛋白Pleckstrin-2(Plek2)或其广泛表达的Paralog Pleckstrin-1(Plek1)， 削弱磷脂酰肌醇3-激酶(PI3K)信号，从而逆转许多 JAK2V617F敲击小鼠广泛的血管闭塞和致死性。基于这些 研究表明，我们推测这两种Pleckstrin亚型对血栓的形成都是至关重要的。 在JAK2V617F驱动的疾病中，通过磷脂酰肌醇介导的途径。的目标 这一建议是为了：(1)实现对JAK2-如何驱动的机械性理解 MPN疾病中的血栓形成，以及(2)确定Plek1和Plek2如何介导 JAK2V617F相关血栓的研究进展更好地理解分子 患者发生血栓形成的基础应该对两者都有深远的影响 JAK2V617F致病患者的认识和治疗。