Molecular Pathogenesis & Therapy of JAK2 V617F-induced Myeloproliferative Disease

分子发病机制

基本信息

批准号：
7597145
负责人：
RICHARD A. VAN ETTEN
金额：
$ 40.25万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7597145
关键词：
A Mouse Acute leukemia Address Anemia Antibodies Bcr-Abl tyrosine kinase Biological Assay Biological Models Biology Bleeding time procedure Blood Clot Blood Coagulation Disorders Blood Platelets Blood coagulation Bone Marrow Cells Cessation of life Chronic Myeloid Leukemia Clinical Coagulation Process Commit Cytogenetics Development Disease Disease remission Drug Delivery Systems Erythrocytes Erythroid Erythropoietin Receptor Event Functional disorder Genetic Goals Hemorrhage Hemorrhagic Thrombocythemia Hemostatic Agents Hemostatic function Human Imatinib Inbred Strains Mice JAK2 gene Knowledge Laboratories Lead Leukocytes Leukocytosis Megakaryocytes Modeling Molecular Morbidity - disease rate Mus Mutation Myelofibrosis Myeloproliferative disease Myelosuppressive Therapy Neutrophilia Pancytopenia Pathogenesis Pathway interactions Patients Phase Philadelphia Chromosome Plasma Platelet Count measurement Polycythemia Polycythemia Vera Primary Myelofibrosis Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Receptor Signaling Red Cell Mass result Reticulocytosis Role Signal Pathway Signaling Molecule Somatic Mutation Stem cells Supportive care Tail Testing Therapeutic Therapeutic Effect Thrombosis Tissues Transfusion Transplantation Venous blood sampling base bcr-abl Fusion Proteins human disease in vivo inhibitor/antagonist kinase inhibitor leukemia mouse model neutrophil progenitor research study retroviral transduction self-renewal src-Family Kinases therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Chronic myeloid leukemia (CML) is a myeloproliferative disease (MPD) associated with BCR-ABL, an activated tyrosine kinase that is the product of the Philadelphia chromosome. A mouse model of CML, where BCR-ABL is expressed by retroviral bone marrow transduction and transplantation, demonstrated that BCR-ABL is the direct cause of CML, and motivated the development of imatinib, an ABL kinase inhibitor that has revolutionized the treatment of CML patients. Polycythemia vera (PV), essential thromobocythemia (ET), and chronic idiopathic myelofibrosis (CIMF) are MPDs that are as prevalent as CML, but their pathogenesis is unclear, and their clinical course is complicated by bleeding, thrombosis, and progression to acute leukemia or bone marrow failure. Current therapy for these MPDs is also inadequate, ranging from phlebotomy and myelosuppressive therapy for PV and ET, to transfusions and supportive care for CIMF. Recently, a somatic activating mutation (V617F) in the JAK2 tyrosine kinase was discovered in most patients with PV and some patients with ET and CIMF. However, the role of JAK2 V617F in the pathogenesis and potential therapy of these diseases is not known. A mouse retroviral transduction/transplantation model of MPD induced by JAK2 V617F has recently been developed by our laboratory. Using the model, it has been demonstrated that JAK2 V617F recapitulates the entire spectrum of erythroid abnormalities of PV in mice, implicating it as the direct and principal cause of human PV. In this application, this model system will be used to address some fundamental questions about the molecular pathogenesis and therapy of JAK2 V617F-induced MPD that would be difficult or impossible to approach through human studies. Specifically, the application proposes to: (1) use a genetic approach to determine the pathways downstream of JAK2 V617F that are required for MPD, with the ultimate goal of validating additional therapeutic targets; and (2) test the therapeutic activity of molecularly targeted drugs in JAK2 V617F-induced MPD, including candidate JAK2 inhibitors. These experiments will yield new knowledge about the biology and treatment of this important group of MPDs, and should provide important information to guide the clinical development of JAK2 kinase inhibitors and other molecularly targeted therapies for MPD. PROJECT NARRATIVE: Polycythemia vera (PV) is a human disease where too many red blood cells are produced. Current therapy for PV is inadequate due to blood clotting problems and development of leukemia. In this proposal, a mouse model of PV will be used to better understand the basic cause of PV, and to test new treatments for the disease, which could lead to better treatments for PV patients.

描述（由申请人提供）：慢性粒细胞白血病 (CML) 是一种与 BCR-ABL 相关的骨髓增生性疾病 (MPD)，BCR-ABL 是一种激活的酪氨酸激酶，是费城染色体的产物。通过逆转录病毒骨髓转导和移植表达 BCR-ABL 的 CML 小鼠模型，证明 BCR-ABL 是 CML 的直接原因，并推动了伊马替尼（一种 ABL 激酶抑制剂）的开发，彻底改变了 CML 的治疗患者。真性红细胞增多症 (PV)、原发性血小板增多症 (ET) 和慢性特发性骨髓纤维化 (CIMF) 是与 CML 一样常见的 MPD，但其发病机制尚不清楚，其临床过程因出血、血栓形成和进展为急性白血病而复杂化或骨髓衰竭。目前对这些 MPD 的治疗也不够充分，从针对 PV 和 ET 的放血和骨髓抑制治疗，到针对 CIMF 的输血和支持治疗。最近，在大多数 PV 患者以及一些 ET 和 CIMF 患者中发现了 JAK2 酪氨酸激酶的体细胞激活突变 (V617F)。然而，JAK2 V617F 在这些疾病的发病机制和潜在治疗中的作用尚不清楚。我们实验室最近建立了JAK2 V617F诱导的MPD小鼠逆转录病毒转导/移植模型。使用该模型，已证明 JAK2 V617F 概括了小鼠 PV 红细胞异常的整个范围，表明它是人类 PV 的直接和主要原因。在此应用中，该模型系统将用于解决有关 JAK2 V617F 诱导的 MPD 的分子发病机制和治疗的一些基本问题，这些问题很难或不可能通过人体研究来解决。具体来说，该申请建议：（1）使用遗传方法确定 MPD 所需的 JAK2 V617F 下游通路，最终目标是验证其他治疗靶点； (2)测试分子靶向药物在JAK2 V617F诱导的MPD中的治疗活性，包括候选JAK2抑制剂。这些实验将产生有关这一类重要 MPD 的生物学和治疗的新知识，并为指导 JAK2 激酶抑制剂和其他 MPD 分子靶向疗法的临床开发提供重要信息。项目叙述：真性红细胞增多症 (PV) 是一种产生过多红细胞的人类疾病。由于凝血问题和白血病的发展，目前的真性红斑狼疮治疗是不够的。在该提案中，PV小鼠模型将用于更好地了解PV的基本原因，并测试该疾病的新疗法，这可能会为PV患者带来更好的治疗。