Mechanisms and effects of NF-E2 and PRV-1 overexpression in PV: Role of Jak2V617F
NF-E2 和 PRV-1 在 PV 中过表达的机制和影响:Jak2V617F 的作用
基本信息
- 批准号:7691286
- 负责人:
- 金额:$ 33.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AffectAllelesCell LineageCellsDNA-Protein InteractionDevelopmentDifferentiation and GrowthErythrocytosesFunctional disorderGenesGrowthHematopoiesisHematopoieticHumanIn VitroLeadMalignant - descriptorMediatingModelingMolecularMusMutationPatientsPharmaceutical PreparationsPlayPolycythemia VeraProtein OverexpressionPublic HealthRoleSmall Interfering RNAStem cellsTranscriptional Activationactivating transcription factorbasein vivoknock-downnuclear factor-erythroid 2promoter
项目摘要
The transcription factor NF-E2 and the gene encoding PRV-1 are overexpressed in patients with
polycythemia vera (PV). The recent description of a Jak2V617F mutation in PV patients raises the question
whether this allele exerts its effect on the malignant clone in part through inducing NF-E2 expression. NF-E2
is a promising candidate in the pathophysiology of PV for several reasons:
NF-E2 is overexpressed in stem cells as well as in all three cell lineages affected in PV. In murine cells NFE2
overexpression leads to Epo-independent growth and differentiation. NF-E2 may thus play a pivotal role
in causing the erythrocytosis of PV. However, both the molecular mechanism leading to NF-E2
overexpression and its effect on human hematopoiesis are not known. In addition, the cause of PRV-1
overexpression remains unclear. Therefore, it is the aim of this project to investigate the cause of NF-E2
and PRV-1 overexpression in PV and the effect of NF-E2 overexpression in hematopoietic cells.
Based on the following hypotheses, the specific aims of this project are therefore:
1. Hypothesis: NF-E2 is required for the Epo-independent growth of PV cells or its overexpression
modulates hematopoietic differentiation. Specific Aim: To modulate NF-E2 expression via siRNA knock down
and retroviral or lentiviral transduction and examine the consequences on Epo-dependent and -independent
growth in vitro.
2. Hypothesis: NF-E2 and PRV-1 overexpression in PV are mediated by the Jak2V617F allele Specific Aim:
To introduce Jak2 wt and V617F alleles in vivo and in vitro and examine the effects on NF-E2 and PRV-1
expression in various models.
3. Hypothesis: NF-E2 and PRV-1 overexpression result from aberrant transcriptional activation Specific Aim:
To characterize protein/DNA interaction on the NF-E2 and PRV-1 promoters in PV and healthy control cells
to determine aberrantly activated transcription factors.
Public Health Implications: By leading to a better understanding of the molecular changes that lead to the
development of PV, this project will point out molecules against which new drugs for treatment can be
developed.
转录因子NF-E2和PRV-1编码基因在慢性支气管炎患者中的过度表达
真性红细胞增多症(PV)。最近对PV患者JAK2V617F突变的描述提出了一个问题
该等位基因对恶性克隆的作用部分是通过诱导核因子-E2的表达来实现的。核因子-E2
是PV病理生理学领域很有前途的候选者,原因如下:
核因子-E2在干细胞中以及在PV中受影响的所有三种细胞系中都过表达。在小鼠细胞NFE2中
过度表达导致EPO非依赖的生长和分化。因此,核因子-E2可能起到关键作用。
在引起PV的红细胞增多症方面。然而,导致核因子-E2的分子机制
目前尚不清楚该基因的过度表达及其对人类造血的影响。此外,PRV-1的起因
过度表达仍不清楚。因此,本项目的目的是研究核因子-E2的原因
PV中PRV-1过表达及造血细胞中NF-E2过表达的影响。
因此,基于以下假设,本项目的具体目标是:
1.假设:核因子-E2是PV细胞EPO非依赖性生长或其过度表达所必需的
调节造血分化。特定目的:通过siRNA敲除来调节核因子-E2的表达
和逆转录病毒或慢病毒转导,并检查对EPO依赖和非依赖的后果
在体外生长。
2.假说:PV中NF-E_2和PRV-1的过度表达是由JAK2V617F等位基因特异的目的介导的:
体内、外引入JAK2wt和V617F等位基因并检测其对NF-E2和PRV-1的影响
在不同的模型中表达。
3.假设:核因子-E2和PRV-1的过度表达是转录激活异常的结果特定目的:
PV和健康对照细胞中NF-E2和PRV-1启动子的蛋白质/DNA相互作用特征
以确定异常激活的转录因子。
对公共卫生的影响:通过更好地理解导致
开发光伏,这个项目将指出治疗新药可以针对的分子
发展起来的。
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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Heike L Pahl其他文献
Activators and target genes of Rel/NF-κB transcription factors
Rel/NF-κB 转录因子的激活因子和靶基因
- DOI:
10.1038/sj.onc.1203239 - 发表时间:
1999-11-22 - 期刊:
- 影响因子:7.300
- 作者:
Heike L Pahl - 通讯作者:
Heike L Pahl
Sentinel mutations: the roses in the vineyard.
哨兵突变:葡萄园里的玫瑰。
- DOI:
- 发表时间:
2021 - 期刊:
- 影响因子:20.3
- 作者:
Heike L Pahl - 通讯作者:
Heike L Pahl
Heike L Pahl的其他文献
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{{ truncateString('Heike L Pahl', 18)}}的其他基金
A New Murine Model for MPN: Pathololgy and Therapy of NF-E2 Overexpression
MPN 的新小鼠模型:NF-E2 过度表达的病理学和治疗
- 批准号:
8377870 - 财政年份:2006
- 资助金额:
$ 33.94万 - 项目类别:
A New Murine Model for MPN: Pathololgy and Therapy of NF-E2 Overexpression
MPN 的新小鼠模型:NF-E2 过度表达的病理学和治疗
- 批准号:
8533749 - 财政年份:2006
- 资助金额:
$ 33.94万 - 项目类别:
A New Murine Model for MPN: Pathololgy and Therapy of NF-E2 Overexpression
MPN 的新小鼠模型:NF-E2 过度表达的病理学和治疗
- 批准号:
8722847 - 财政年份:2006
- 资助金额:
$ 33.94万 - 项目类别:
A New Murine Model for MPN: Pathololgy and Therapy of NF-E2 Overexpression
MPN 的新小鼠模型:NF-E2 过度表达的病理学和治疗
- 批准号:
8064159 - 财政年份:2006
- 资助金额:
$ 33.94万 - 项目类别:
Mechanisms and effects of NF-E2 and PRV-1 overexpression in PV: Role of Jak2V617F
NF-E2 和 PRV-1 在 PV 中过表达的机制和影响:Jak2V617F 的作用
- 批准号:
7912878 - 财政年份:
- 资助金额:
$ 33.94万 - 项目类别:
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