JAK2 signaling in erythropoiesis
红细胞生成中的 JAK2 信号传导
基本信息
- 批准号:8512914
- 负责人:
- 金额:$ 37.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-09-01 至 2018-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAnemiaBiologyBlood CellsBlood SubstitutesCatalytic DomainChIP-seqChromatin StructureClinical DataComplexCytokine ReceptorsDefectDevelopmentEZH2 geneEndocytosisEpigenetic ProcessErythrocytesErythrocytosesErythroidErythropoiesisErythropoietin ReceptorEtiologyEventExhibitsExonsFeedbackFunctional disorderFundingGene ExpressionGene TargetingGenerationsGenetic TranscriptionGoalsGranulopoiesisHematologic NeoplasmsHematopoiesisHematopoieticHumanIn VitroInvestigationKnowledgeLigandsLightMediatingModelingMolecularMusMutationMyeloproliferative diseasePathway interactionsPatientsPhenotypePhosphorylationPhosphorylation SitePhosphotransferasesPlayPolycombPolycythemiaProcessProductionProtein Tyrosine KinaseProteinsRecruitment ActivityRegulationRepressionRoleSTAT5A geneSignal PathwaySignal TransductionStem cellsSystemTestingTherapeutic AgentsToxic effectTranslatingWorkchromatin immunoprecipitationdesigneffective therapyepsinerythroid differentiationgain of functiongenome wide association studygenome-widegranulocyteimprovedin vitro activityin vivokinase inhibitorknowledge basemouse modelmutantnovelnovel therapeuticsprogenitorpublic health relevanceresearch studystem
项目摘要
DESCRIPTION (provided by applicant): The Janus tyrosine kinase 2 (JAK2) plays an important role in hematopoiesis of multiple lineages, and a gain-of-function JAK2 mutation, V617F, is the major determinant in myeloproliferative neoplasms (MPNs). JAK2 kinase inhibitors showed hematological toxicity in treating MPNs, calling for novel therapeutics that can target only the affected lineage while sparing others. This task is hampered by lack of understanding in how JAK2 signaling regulates the generation of different blood cells. We propose to fill this knowledge gap by determining JAK2 signaling pathways that differentially drive erythropoiesis vs. granulopoiesis, and delineate two novel pathways utilized by JAK2 to regulate signaling and transcription for erythroid differentiation. The overall goal of this proposl is to characterize mechanisms underlying how JAK2 regulates erythropoiesis. Aim 1 will characterize a novel set of murine models; each expresses a different activating JAK2 mutant that results in a distinct MPN phenotype. We will determine whether different JAK2 mutants cause erythrocytosis or granulocytosis by promoting lineage-specific proliferation or by skewing differentiation in common progenitor compartments, and identify downstream signaling pathways required therein to cause different MPN phenotypes. We will also translate these mechanistic studies into the human setting. Aims 2 and 3 will dissect two novel molecular mechanisms for JAK2 to orchestrate signaling and transcription for erythroid differentiation, and examine their contribution in MPN development. Aim 2 will use both in vitro and in vivo experiments to characterize how JAK2 directs endocytosis of the erythropoietin receptor to terminate signaling. This process involves a new function of the p85 subunit of PI3K and is PI3K kinase activity-independent. Defects in this process result in prolonged signaling in primary and familial congenital polycythemia. In Aim 3, we will employ transcriptional profiling and genome-wide chromatin-immunoprecipitation followed by high-throughput sequencing (ChIP-seq) to delineate a novel pathway whereby JAK2 controls transcription, not by the canonical JAK-STAT pathway, but by regulating chromatin structure through phosphorylating the polycomb repression complex 2. Results from these studies will fill key gaps in our understanding of signaling in hematopoietic stem and progenitor cells that regulate both normal and excessive erythropoiesis. These results will also further our understanding of how Epo signaling is terminated, and will shift the paradigm of how JAK2 activates erythroid transcriptional network. In addition, these results will shed light on MPN biology and facilitate the design of novel and more effective therapeutic agents that specifically target affected lineage without compromising other lineages.
描述(由申请人提供):Janus酪氨酸激酶2(JAK 2)在多个谱系的造血中起重要作用,JAK 2功能获得性突变V617 F是骨髓增生性肿瘤(MPN)的主要决定因素。JAK 2激酶抑制剂在治疗MPN时显示出血液学毒性,这就需要一种新的治疗方法,这种方法只能靶向受影响的谱系,而不影响其他谱系。由于缺乏对JAK 2信号传导如何调节不同血细胞生成的了解,这项任务受到阻碍。我们建议通过确定JAK 2信号通路来填补这一知识空白,JAK 2信号通路差异驱动红细胞生成与粒细胞生成,并描绘出JAK 2用于调节红细胞分化的信号传导和转录的两种新途径。该提议的总体目标是表征JAK 2如何调节红细胞生成的潜在机制。目的1将表征一组新的小鼠模型;每个模型表达不同的激活JAK 2突变体,导致不同的MPN表型。我们将确定不同的JAK 2突变体是否通过促进谱系特异性增殖或通过在共同祖细胞隔室中的偏斜分化引起红细胞增多症或粒细胞增多症,并确定其中引起不同MPN表型所需的下游信号传导途径。我们还将把这些机械研究转化为人类环境。目的2和3将剖析JAK 2协调红细胞分化的信号传导和转录的两种新的分子机制,并研究它们在MPN发育中的作用。目的2将使用体外和体内实验来表征JAK 2如何指导促红细胞生成素受体的内吞作用以终止信号传导。该过程涉及PI 3 K的p85亚基的新功能,并且是PI 3 K激酶活性不依赖的。这一过程的缺陷导致原发性和家族性先天性红细胞增多症中信号传导延长。在目标3中,我们将采用转录谱分析和全基因组染色质免疫沉淀,然后进行高通量测序(ChIP-seq)来描绘一种新的途径,JAK 2通过这种途径控制转录,而不是通过经典的JAK-STAT途径,而是通过磷酸化多梳抑制复合物2来调节染色质结构。这些研究的结果将填补我们对造血干细胞和祖细胞中调节正常和过度红细胞生成的信号传导的理解中的关键空白。这些结果也将进一步加深我们对Epo信号是如何终止的理解,并将改变JAK 2如何激活红细胞转录网络的范式。此外,这些结果将揭示MPN生物学,并促进设计新的和更有效的治疗剂,专门针对受影响的谱系,而不损害其他谱系。
项目成果
期刊论文数量(0)
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LILY JUNSHEN HUANG其他文献
LILY JUNSHEN HUANG的其他文献
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{{ truncateString('LILY JUNSHEN HUANG', 18)}}的其他基金
Erythropoietin receptor signaling in erythropoiesis
红细胞生成中的促红细胞生成素受体信号传导
- 批准号:
7837446 - 财政年份:2009
- 资助金额:
$ 37.84万 - 项目类别:
Erythropoietin receptor signaling in erythropoiesis
红细胞生成中的促红细胞生成素受体信号传导
- 批准号:
7320425 - 财政年份:2007
- 资助金额:
$ 37.84万 - 项目类别:
Erythropoietin receptor signaling in erythropoiesis
红细胞生成中的促红细胞生成素受体信号传导
- 批准号:
8081753 - 财政年份:2007
- 资助金额:
$ 37.84万 - 项目类别:
Erythropoietin receptor signaling in erythropoiesis
红细胞生成中的促红细胞生成素受体信号传导
- 批准号:
7659642 - 财政年份:2007
- 资助金额:
$ 37.84万 - 项目类别:
Erythropoietin receptor signaling in erythropoiesis
红细胞生成中的促红细胞生成素受体信号传导
- 批准号:
7463849 - 财政年份:2007
- 资助金额:
$ 37.84万 - 项目类别:
Erythropoietin receptor signaling in stress erythropoiesis and erythrocytosis
应激性红细胞生成和红细胞增多中的促红细胞生成素受体信号传导
- 批准号:
10311980 - 财政年份:2007
- 资助金额:
$ 37.84万 - 项目类别:
Erythropoietin receptor signaling in stress erythropoiesis and erythrocytosis
应激性红细胞生成和红细胞增多中的促红细胞生成素受体信号传导
- 批准号:
10658667 - 财政年份:2007
- 资助金额:
$ 37.84万 - 项目类别:
Erythropoietin receptor signaling in erythropoiesis
红细胞生成中的促红细胞生成素受体信号传导
- 批准号:
7911774 - 财政年份:2007
- 资助金额:
$ 37.84万 - 项目类别:
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