The role of Abelson interactor 1 (Abi-1) in hematopoietic stem cell self-renewal and malignant transformation
Abelson相互作用子1(Abi-1)在造血干细胞自我更新和恶性转化中的作用
基本信息
- 批准号:10651698
- 负责人:
- 金额:$ 36.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-24 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAdaptor Signaling ProteinAffectAttentionBloodBone MarrowCell Proliferation RegulationCellsClinicalCommunicationComplementCritical PathwaysDataDevelopmentDiseaseEmbryoEventGenesGenetic Complementation TestGoalsHeart AbnormalitiesHematopoieticHematopoietic SystemHematopoietic stem cellsHomeostasisHumanImpairmentInflammationInflammatoryJAK2 geneKnockout MiceKnowledgeLabelMAP Kinase GeneMaintenanceMalignant - descriptorMediatingModelingMusMutationMyeloproliferative diseaseNF-kappa BNeoplasmsPathogenesisPathogenicityPathway interactionsPatientsPhenotypePhosphotransferasesPlacentaPlayPolymersPrimary MyelofibrosisProcessProteinsProteomicsRegulationResearchRoleSTAT3 geneSignal PathwaySignal TransductionTechnologyTestingTherapeuticTranscriptcancer stem cellcurative treatmentsdisease natural historyfitnessgranulocytehematopoietic stem cell self-renewalinhibitorinsightmouse modelnovelnovel therapeutic interventionphosphoproteomicspolymerizationresponseself-renewalsrc-Family Kinasesstem cellstherapeutic targettranslational goal
项目摘要
PROJECT SUMMARY/ABSTRACT
It is well established that JAK/STAT signaling is dysregulated in most myeloid malignancies. Identification of
JAK-activating mutations in myeloproliferative neoplasms (MPNs) prompted the development of inhibitors that
target JAK for use in the clinical setting. While these agents provide a symptomatic response, they do not alter
the underlying disease in that they do not target MPN-initiating malignant hematopoietic stem/progenitor cells
(HSPCs). This observation has been interpreted as indicating that alternative signaling pathways contribute to
the pathogenesis of MPNs. The present proposal is based on the premise that identification of hitherto
unknown pathogenic mechanisms will be required to effectively treat these neoplasms and eradicate disease
initiating MPN stem cells. Our long-term goal is to define signal transduction events responsible for systemic
maintenance of HSPCs, with particular focus on key adapter proteins that modulate signals regulating HSPCs
self-renewal, differentiation and their malignant transformation. Our direct objective is to elucidate the role of
one such adapter protein, Abelson interactor-1 (Abi-1), in signaling cascades that define the HSPC phenotype.
Our recent findings indicate that: (1) conditional deletion of the Abi1 gene in mouse bone marrow induces a
myelofibrotic phenotype; (2) hematopoietic progenitors and granulocytes from patients with the most severe of
MPNs - primary myelofibrosis (PMF) show decreased Abi-1 transcript and protein levels, and; (3) loss of Abi-1
positively affects the activity of Src Family Kinases (SFKs) and their downstream signaling to STAT3 and NF-
κB, resulting in impairment of HSPC self-renewal and fitness. Our central hypothesis is that Abi-1 plays
an important and potentially targetable role in HSPC self-renewal and differentiation via negative regulation of
the SFK/STAT3/NF-κB inflammatory module, and that its acquired absence can promote malignant
transformation and progression to PMF. Our central hypothesis will be tested in the following three Specific
Aims. In Specific Aim 1 we will use our new hematopoietic cell-specific Abi-1 knockout mouse model to
determine the effect of Abi-1 loss on HSPC signaling and self-renewal, differentiation and malignant
transformation. In Specific Aim 2, we will use advanced proteomics combined with proximity-dependent
labelling technology to define the Abi-1 interactome in HSPCs. This approach will be complemented by
phosphoproteomic analyses of Abi-1-deficient HSPCs and human PMF stem/progenitor cells. In Specific Aim
3 we will use our bone marrow stroma-specific Abi-1 knockout mouse model to assess the effect of deletion of
Abi-1 in the stromal component on the self-renewal, differentiation and malignant transformation of HSPCs.
Completion of the proposed aims will advance our understanding of the mechanisms by which dysregulation of
Abi-1/SFK/STAT3/NF-kB signaling contributes to the neoplasm-inducing capacities of HSPCs. This new
knowledge will be used to make progress toward our long-term translational goal of identifying therapeutic
strategies that target cells responsible for the origin of myeloproliferative neoplasms.
项目摘要/摘要
众所周知,在大多数骨髓恶性肿瘤中,JAK/Stat信号传导失调。识别
骨髓增生性肿瘤(MPN)中的JAK激活突变引发了抑制剂的发展
靶标JAK用于临床环境。尽管这些代理人提供症状反应,但它们不会改变
潜在疾病是因为它们不靶向MPN引发恶性造血/祖细胞
(HSPC)。该观察结果已解释为表明替代信号通路有助于
MPN的发病机理。本提案基于以下前提
将需要未知的致病机制有效治疗这些肿瘤和放射性疾病
引发MPN干细胞。我们的长期目标是定义负责系统性的信号转导事件
HSPC的维护,特别关注关键适配器蛋白,该蛋白调节调节HSPC的信号
自我更新,分化及其恶性转变。我们的直接目标是阐明
一种此类衔接蛋白Abelson Intercontor-1(ABI-1)在定义HSPC表型的信号级联反应中。
我们最近的发现表明:(1)小鼠骨髓中ABI1基因的条件缺失诱导A
骨髓纤维化表型; (2)来自最严重的患者的造血祖细胞和粒细胞
MPN-原发性骨髓纤维化(PMF)显示ABI -1转录本和蛋白质水平降低,并且; (3)ABI-1的丢失
积极影响SRC家族激酶(SFK)的活性及其下游信号对STAT3和NF-
κB,导致HSPC自我更新和适应性受损。我们的中心假设是ABI-1播放
通过负调节,在HSPC自我更新和分化中的重要且潜在的目标作用
SFK/STAT3/NF-κB炎症模块,其获得的缺失可以促进恶性肿瘤
转化和发展向PMF。我们的中心假设将在以下三个特定中进行检验
目标。在特定目标1中,我们将使用我们的新造血细胞特异性ABI-1敲除鼠标模型
确定ABI-1损失对HSPC信号传导和自我更新,分化和恶性的影响
转型。在特定的目标2中,我们将使用高级蛋白质组学与邻近性相关性
标记技术以定义HSPC中的ABI-1 Intervortome。这种方法将由
ABI-1缺陷HSPC和人PMF茎/祖细胞的磷酸蛋白质组学分析。在特定目标中
3我们将使用骨髓特异性ABI-1敲除小鼠模型来评估缺失的影响
HSPC的自我更新,分化和恶性转化的基质成分中的ABI-1。
拟议目标的完成将提高我们对失调失调机制的理解
ABI-1/SFK/STAT3/NF-KB信号传导有助于HSPC的肿瘤诱导能力。这个新
知识将用于朝着我们识别治疗的长期翻译目标取得进步
靶向负责骨髓增生肿瘤起源的策略。
项目成果
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Patrycja Marta Dubielecka-Szczerba其他文献
Patrycja Marta Dubielecka-Szczerba的其他文献
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{{ truncateString('Patrycja Marta Dubielecka-Szczerba', 18)}}的其他基金
The role of Abelson interactor 1 (Abi-1) in hematopoietic stem cell self-renewal and malignant transformation
Abelson相互作用子1(Abi-1)在造血干细胞自我更新和恶性转化中的作用
- 批准号:
10197837 - 财政年份:2019
- 资助金额:
$ 36.09万 - 项目类别:
The role of Abelson interactor 1 (Abi-1) in hematopoietic stem cell self-renewal and malignant transformation
Abelson相互作用子1(Abi-1)在造血干细胞自我更新和恶性转化中的作用
- 批准号:
9982974 - 财政年份:2019
- 资助金额:
$ 36.09万 - 项目类别:
The role of Abelson interactor 1 (Abi-1) in hematopoietic stem cell self-renewal and malignant transformation
Abelson相互作用子1(Abi-1)在造血干细胞自我更新和恶性转化中的作用
- 批准号:
10411385 - 财政年份:2019
- 资助金额:
$ 36.09万 - 项目类别:
The role of Abelson interactor 1 (Abi-1) in hematopoietic stem cell self-renewal and malignant transformation
Abelson相互作用子1(Abi-1)在造血干细胞自我更新和恶性转化中的作用
- 批准号:
10447020 - 财政年份:2019
- 资助金额:
$ 36.09万 - 项目类别:
The role of Abelson interactor 1 (Abi-1) in hematopoietic stem cell self-renewal and malignant transformation
Abelson相互作用子1(Abi-1)在造血干细胞自我更新和恶性转化中的作用
- 批准号:
10524088 - 财政年份:2019
- 资助金额:
$ 36.09万 - 项目类别:
Interrogating the Role of Abelson Interactor 1 in Age-Related Myelofibrosis
探讨 Abelson Interactor 1 在年龄相关性骨髓纤维化中的作用
- 批准号:
10210269 - 财政年份:2017
- 资助金额:
$ 36.09万 - 项目类别:
Interrogating the Role of Abelson Interactor 1 in Age-Related Myelofibrosis
探讨 Abelson Interactor 1 在年龄相关性骨髓纤维化中的作用
- 批准号:
9356957 - 财政年份:
- 资助金额:
$ 36.09万 - 项目类别:
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