Targeting of IL-1 Signaling in Myelofibrosis

骨髓纤维化中 IL-1 信号传导的靶向

• 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
• 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

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信号转导的靶向 项目总结/摘要 骨髓增生性肿瘤（MPN），包括真性红细胞增多症（PV）、原发性血小板增多症（ET）和 骨髓纤维化（MF）是一组克隆性造血干细胞衍生的骨髓恶性肿瘤，其特征在于 是由于骨髓细胞的过度增殖。MF是MPN中最致命的。患者的中位生存期 MF是5年。约95%的PV和约50-60%的PV患者存在JAK 2 V617 F突变， 的和MF。血小板生成素受体（MPL）和钙网蛋白（CALR）的突变也被检测到。 MF。目前批准的JAK抑制剂Ruxolitinib和Fedratinib可以缓解全身症状， 它们不能显著改善骨髓纤维化。因此，有一个未得到满足的需要， 新的治疗靶点和开发MF的新疗法。慢性炎症通常与 MPN/MF。MPN/MF中白细胞介素-1（IL-1）的表达升高， 患者以及Jak 2 V617 F基因敲入小鼠中。然而，IL-1信号转导在细胞凋亡中的作用并不明显。 MPN/MF的发病机制仍不清楚。在初步研究中，我们发现， IL-1 R1使外周血计数正常化，减少脾肿大，并显著抑制骨髓 在MF的Jak 2 V617 F基因敲入小鼠模型中的纤维化。因此，我们假设IL-1信号可能在 IL-1在MF发病机制中的重要作用以及IL-1信号转导的靶向作用可能对MF的治疗有用。在 根据该提议，我们将进一步研究IL-1信号传导在MF发病机制中的作用，并测试 在骨髓纤维化的临床前模型中药理学抑制IL-1信号传导的功效。我们还将 确定抑制IL-1信号传导阻止MPN/MF进展的机制。结果 本研究为骨髓纤维化的治疗提供了新的思路。