Targeting of IL-1 Signaling in Myelofibrosis

骨髓纤维化中 IL-1 信号传导的靶向

基本信息

批准号：
10657996
负责人：
Golam Mohi
金额：
$ 18.88万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657996
关键词：
Acute Myelocytic Leukemia Antibodies Applications Grants Binding Bone Marrow Bone Marrow Cells Cell Lineage Cells Chronic Clonal Expansion Clonal Hematopoietic Stem Cell Collagen Constitutional Symptom Data Development Disease remission Drug Combinations Effectiveness Exhibits Genes Genetic Goals Hematologic Neoplasms Hematological Disease Hematopoietic Hematopoietic stem cells Hemorrhagic Thrombocythemia Heterozygote Human Inflammation Interleukin-1 Interleukin-1 Receptors JAK2 gene Knock-in Knock-in Mouse MAP Kinase Gene MPL gene Mediating Modeling Molecular Mus Mutation Myelofibrosis Myelogenous Myeloid Cells Myeloproliferative disease Oncogenic Pathogenesis Pathway interactions Patients Penetrance Play Polycythemia Vera Pre-Clinical Model Production Prognosis Role Signal Transduction Splenomegaly Testing Time Treatment Failure Work anakinra calreticulin chemotherapy cytokine effectiveness testing efficacy testing expectation improved inhibitor knock-down mesenchymal stromal cell mouse model mutant new therapeutic target novel strategies novel therapeutic intervention novel therapeutics p38 Mitogen Activated Protein Kinase peripheral blood pharmacologic prevent small hairpin RNA transcriptome sequencing treatment effect treatment strategy

项目摘要

Title: Targeting of IL-1 Signaling in Myelofibrosis PROJECT SUMMARY/ABSTRACT Myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) are a group of clonal hematopoietic stem cell derived myeloid malignancies characterized by overproduction of myeloid lineage cells. MF is the deadliest among MPNs. The median survival of patients with MF is ~5 years. The oncogenic JAK2V617F mutation was found in ~95% cases of PV and ~50-60% cases of ET and MF. Mutations in the thrombopoietin receptor (MPL) and calreticulin (CALR) were also detected in MF. Currently approved JAK inhibitors, Ruxolitinib and Fedratinib, can alleviate constitutional symptoms but they do not offer significant improvement of bone marrow fibrosis. Therefore, there is an unmet need to identify new therapeutic targets and develop novel therapies for MF. Chronic inflammation is frequently associated with MPN/MF. Expression of interleukin-1 (IL-1), a master regulator of inflammation, is found elevated in MPN/MF patients as well as in Jak2V617F knock-in mice. However, the contribution of IL-1 signaling in the pathogenesis of MPN/MF has remained elusive. In preliminary studies, we have found that genetic deletion of IL-1R1 normalizes peripheral blood counts, reduces splenomegaly and significantly inhibits bone marrow fibrosis in a Jak2V617F knock-in mouse model of MF. So, we hypothesize that IL-1 signaling may play an important role in the pathogenesis of MF and targeting of IL-1 signaling might be useful for treatment of MF. In this proposal, we will further investigate the contribution of IL-1 signaling in the pathogenesis of MF and test the efficacy of pharmacologic inhibition of IL-1 signaling in pre-clinical models of myelofibrosis. We will also determine the mechanism by which inhibition of IL-1 signaling prevents the progression of MPN/MF. Results from this study may lead to new therapeutic approach for treatment of myelofibrosis.

标题：骨髓纤维化中IL-1信号的靶向项目摘要/摘要脊髓增生性肿瘤（MPN），包括多余的Vera（PV），必需血小板炎（ET）和骨髓纤维化（MF）是一组衍生出的髓样恶性肿瘤的克隆造血干细胞通过过量生产髓样谱系细胞。 MF是MPN中最致命的。患者的中位生存期 MF约5年。在〜95％的PV病例和约50-60％的病例中发现了致癌JAK2V617F突变 ET和MF。还检测 MF。目前批准的JAK抑制剂Ruxolitinib和Fedratinib可以减轻宪法症状，但它们不能显着改善骨髓纤维化。因此，有未满足的需要识别新的治疗靶点并开发了MF的新型疗法。慢性炎症经常与 MPN/MF。在MPN/MF中发现白介素-1（IL-1）的表达是炎症的主要调节剂患者以及JAK2V617F敲门小鼠。但是，IL-1信号在 MPN/MF的发病机理仍然难以捉摸。在初步研究中，我们发现遗传缺失的 IL-1R1使外周血计数归一化，减少脾肿大并显着抑制骨髓 MF的JAK2V617F敲入小鼠模型中的纤维化。因此，我们假设IL-1信号可能会播放在MF的发病机理和IL-1信号传导的靶向中，重要作用可能对治疗MF有用。在该提案，我们将进一步研究IL-1信号在MF发病机理和测试中的贡献药理学抑制IL-1信号传导在骨髓纤维化前模型中的功效。我们也会确定抑制IL-1信号传导阻止MPN/MF的进展的机制。结果从这项研究中，可能导致新的治疗方法来治疗骨髓纤维化。