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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：
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
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/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

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）是一种促血栓形成的恶性肿瘤