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:
- 金额:$ 18.88万
- 依托单位:
- 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:
- 关键词:Acute Myelocytic LeukemiaAntibodiesApplications GrantsBindingBone MarrowBone Marrow CellsCell LineageCellsChronicClonal ExpansionClonal Hematopoietic Stem CellCollagenConstitutional SymptomDataDevelopmentDisease remissionDrug CombinationsEffectivenessExhibitsGenesGeneticGoalsHematologic NeoplasmsHematological DiseaseHematopoieticHematopoietic stem cellsHemorrhagic ThrombocythemiaHeterozygoteHumanInflammationInterleukin-1Interleukin-1 ReceptorsJAK2 geneKnock-inKnock-in MouseMAP Kinase GeneMPL geneMediatingModelingMolecularMusMutationMyelofibrosisMyelogenousMyeloid CellsMyeloproliferative diseaseOncogenicPathogenesisPathway interactionsPatientsPenetrancePlayPolycythemia VeraPre-Clinical ModelProductionPrognosisRoleSignal TransductionSplenomegalyTestingTimeTreatment FailureWorkanakinracalreticulinchemotherapycytokineeffectiveness testingefficacy testingexpectationimprovedinhibitorknock-downmesenchymal stromal cellmouse modelmutantnew therapeutic targetnovel strategiesnovel therapeutic interventionnovel therapeuticsp38 Mitogen Activated Protein Kinaseperipheral bloodpharmacologicpreventsmall hairpin RNAtranscriptome sequencingtreatment effecttreatment 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.
题目:IL-1信号在骨髓纤维化中的靶向作用
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Golam Mohi', 18)}}的其他基金
Molecular Basis for Myelodysplasia Induced by U2AF1 Mutations
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- 批准号:
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Efficacy of Allosteric SHP2 Inhibitor in RAS Mutant-Driven Myeloid Neoplasms
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9815636 - 财政年份:2019
- 资助金额:
$ 18.88万 - 项目类别:
Targeting of Tyrosine Phosphatase SHP2 in Myeloproliferative Neoplasms
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- 批准号:
9025334 - 财政年份:2015
- 资助金额:
$ 18.88万 - 项目类别:
Inhibition of Histone Deacetylase in Myeloproliferative Neoplasms
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Efficacy of Histone Deacetylase Inhibitor Vorinostat in Myeloproliferative Neopla
组蛋白脱乙酰酶抑制剂伏立诺他在骨髓增生性肿瘤中的疗效
- 批准号:
8049817 - 财政年份:2011
- 资助金额:
$ 18.88万 - 项目类别:
Role of JAK2V617F in the Pathogenesis of Myeloproliferative Neoplasms
JAK2V617F 在骨髓增生性肿瘤发病机制中的作用
- 批准号:
9566613 - 财政年份:2009
- 资助金额:
$ 18.88万 - 项目类别:
Role of JAK2V617F in the Pathogenesis of Myeloproliferative Disorders.
JAK2V617F 在骨髓增殖性疾病发病机制中的作用。
- 批准号:
8043588 - 财政年份:2009
- 资助金额:
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