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：
10187644
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
项目类别：
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/10187644
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

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）是由促血管性恶性肿瘤。髓样细胞的克隆膨胀。 MPN患者的危害比类似于吸烟者的动脉血栓形成及其发展风险静脉血栓形成与V leiden杂合子相当。超过100,000 由于JAK2V617F，美国人患有骨髓增生性障碍，这是一种激活的突变 JAK2酪氨酸激酶。此外，JAK2V617F突变是克隆的驱动器造血症可能存在于多达3％的一般人群中。即使什么时候患者只有血液计数正常的克隆造血作用，JAK2V617F突变仍然赋予了在早期发展心肌梗塞的风险增加12倍。尽管在我们对失调的理解中取得了显着进步 JAK2V617F驱动骨髓增生性疾病的患者的造血作用，非常明显对于为什么患有JAK2V617F突变的患者的分子基础知之甚少有这样的高风险。我们发现老鼠和人类与JAK2V617F 突变形式的血栓在结构和机械上与正常对照不同。具体而言，我们的初步数据表明JAK2V617F突变会诱导较大的凝块由于这些凝块无法紧凑（即缩回）。此外，这些块失败了稳定是因为它们无法用纤维蛋白覆盖表面，从而使凝块更多易碎。因为这些凝块的尺寸较大，所以这使它们更有可能阻塞血管内的血液流动，这些凝块的易碎结构也使它们成为更可能栓塞。我们还观察到磷酸肌醇的损失适配器蛋白，PLECKSTRIN-2（PLEK2）或其广泛表达的旁系同源物pleckstrin-1（plek1），损害磷脂酰肌醇3-激酶（PI3K）信号，从而逆转了许多 JAK2V617F敲击蛋白小鼠的广泛血管闭塞和致死性。基于这些研究，我们假设两个斑丝网同工型对于血栓形成至关重要在JAK2V617F中，通过磷酸肌醇介导的途径驱动疾病。目标该建议是：（1）对JAK2驱动的方式实现机械理解 MPN疾病中的血栓形成，（2）确定plek1和plek2如何介导 JAK2V617F相关的血栓的开发。更好地理解分子为何患者发展血栓形成应该对这两者产生远距离影响的基础了解和治疗JAK2V617F驱动疾病的患者。