Control of the Erythroid Terminal Differentiation Decision

红细胞终末分化决策的控制

基本信息

  • 批准号:
    8512590
  • 负责人:
  • 金额:
    $ 35.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-08-01 至 2017-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to elucidate the factors and mechanisms that control the decision of early erythroid progenitors to undertake terminal differentiation. Much evidence suggests that a crucial aspect of differentiation decisions is a requirement for coordination with the cell proliferation program. However, our current knowledge about the connections between the cell proliferation and differentiation programs is very limited. Work from our lab and others has identified the Ets - family transcription factor PU.1 as a key regulator of the terminal differentiation decision in early erythroid progenitors. And yet, the factors that control PU.1 expression and activity in these early erythroid progenitors and the mechanisms that link the differentiation decision to the cell cycle are not known. Recently, we identified two types of factors that have a very strong potential for connecting PU.1 and the terminal differentiation decision to the cell cycle. One factor is CDK6, which we discovered inhibits erythroid differentiation, like PU.1. We also showed that: 1) CDK6 is the active G1 phase D-cyclin kinase in erythroid progenitors; 2) PU.1 controls transcription of the CDK6 gene; 3) CDK6 phosphorylates PU.1. The other factors are E2F2 and E2F4, transcriptions factors that play major roles in G1 to S phase cell cycle progression. We found that E2F2 and E2F4 occupy the promoter and upstream regulatory element (URE) of the PU.1 gene in erythroid progenitors. They also bind very close to PU.1 at many other PU.1 target genes in these cells. In Aims 1 and 2, we propose a series of experiments to determine how CDK6 and E2F2 and E2F4 influence PU.1 expression and activity and how they collaborate with PU.1 in the erythroid terminal differentiation decision. We also propose to investigate roles for CDK6 and E2F2 in stress erythropoiesis and in ex vivo self-renewal of erythroid precursors. Work from our lab and others showed that one of the principal mechanisms used by PU.1 to regulate the erythroid differentiation decision is repression of erythroid-specific gene expression Recently, we discovered that PU.1 forms a complex with the chromatin remodeling ATPase SNF2H and the maintenance DNA methyltransferase DNMT1; two enzymes that we hypothesize help PU.1 to repress erythroid gene expression. In Aim 3, we propose studies to elucidate the role of SNF2H and DNMT1 in PU.1-mediated repression of erythroid-specific genes and inhibition of erythroid terminal differentiation. The successful completion of the proposed studies will lead to new insights into the mechanisms connecting the proliferation and differentiation programs in hematopoietic cells and a much deeper understanding of how the hematopoietic system regulates red blood cell production, including during ontogeny and in stress conditions. The proposed work will also provide important information enabling the development of new approaches to managing defects in red blood cell production that occur in chronic and acute anemia.
描述(由申请人提供):本项目的总体目标是阐明控制早期红系祖细胞进行终末分化的决定的因素和机制。许多证据表明,差异化决策的一个关键方面 是与细胞增殖计划协调的要求。然而,我们目前对细胞增殖和分化程序之间的联系的了解非常有限。我们实验室和其他人的工作已经确定Ets家族转录因子PU.1是早期红细胞祖细胞终末分化决定的关键调节因子。然而,在这些早期红系祖细胞中控制PU.1表达和活性的因素 并且将分化决定与细胞周期联系起来的机制尚不清楚。最近,我们确定了两种类型的因子,它们具有将PU.1和终末分化决定与细胞周期联系起来的非常强大的潜力。一个因子是CDK 6,我们发现它抑制红细胞分化,就像PU.1一样。我们还表明:1)CDK 6是红系祖细胞中的活性G1期D-细胞周期蛋白激酶; 2)PU.1控制CDK 6基因的转录; 3)CDK 6磷酸化PU.1。其他因子是E2 F2和E2 F4,它们是在G1至S期细胞周期进展中起主要作用的转录因子。我们发现E2 F2和E2 F4占据了红系祖细胞中PU. 1基因的启动子和上游调控元件(URE)。它们还在这些细胞中的许多其他PU.1靶基因处与PU.1非常接近地结合。在目标1和2中,我们提出了一系列实验来确定CDK 6和E2 F2和E2 F4如何影响PU.1表达和活性,以及它们如何在红系终末分化决定中与PU.1协作。我们还建议研究CDK 6和E2 F2在应激红细胞生成和红系前体细胞体外自我更新中的作用。我们实验室和其他人的工作表明,PU.1用于调节红系分化决定的主要机制之一是抑制红系特异性基因表达最近,我们发现PU.1与染色质重塑ATP酶SNF 2 H和维持DNA甲基转移酶DNMT 1形成复合物;我们假设这两种酶有助于PU.1抑制红系基因表达。在目的3中,我们提出研究以阐明SNF 2 H和DNMT 1在PU.1介导的红系特异性基因的阻遏和红系终末分化的抑制中的作用。拟议研究的成功完成将导致对造血细胞增殖和分化程序的机制的新见解,以及对造血系统如何调节红细胞产生的更深入理解,包括在个体发育和应激条件下。拟议的工作还将提供重要的信息,使新的方法来管理发生在慢性和急性贫血的红细胞生成缺陷的发展。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

ARTHUR I SKOULTCHI其他文献

ARTHUR I SKOULTCHI的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('ARTHUR I SKOULTCHI', 18)}}的其他基金

Functions of Mammalian H1 Linker Histones in Gene Regulation and Chromatin Activity
哺乳动物 H1 连接组蛋白在基因调控和染色质活性中的功能
  • 批准号:
    10796397
  • 财政年份:
    2022
  • 资助金额:
    $ 35.05万
  • 项目类别:
Functions of Mammalian H1 Linker Histones in Gene Regulation and Chromatin Activity
哺乳动物 H1 连接组蛋白在基因调控和染色质活性中的功能
  • 批准号:
    10703445
  • 财政年份:
    2022
  • 资助金额:
    $ 35.05万
  • 项目类别:
Functions of Mammalian H1 Linker Histones in Gene Regulation and Chromatin Activity
哺乳动物 H1 连接组蛋白在基因调控和染色质活性中的功能
  • 批准号:
    10502018
  • 财政年份:
    2022
  • 资助金额:
    $ 35.05万
  • 项目类别:
Control of the Erythroid Terminal Differentiation Decision
红细胞终末分化决策的控制
  • 批准号:
    8344044
  • 财政年份:
    2012
  • 资助金额:
    $ 35.05万
  • 项目类别:
Control of the Erythroid Terminal Differentiation Decision
红细胞终末分化决策的控制
  • 批准号:
    8667435
  • 财政年份:
    2012
  • 资助金额:
    $ 35.05万
  • 项目类别:
Control of the Erythroid Terminal Differentiation Decision
红细胞终末分化决策的控制
  • 批准号:
    8874965
  • 财政年份:
    2012
  • 资助金额:
    $ 35.05万
  • 项目类别:
Drosophila Linker Histone H1 Functions in Chromosome Architecture and Activity
果蝇连接组蛋白 H1 在染色体结构和活性中的功能
  • 批准号:
    8213482
  • 财政年份:
    2011
  • 资助金额:
    $ 35.05万
  • 项目类别:
Drosophila Linker Histone H1 Functions in Chromosome Architecture and Activity
果蝇连接组蛋白 H1 在染色体结构和活性中的功能
  • 批准号:
    8403016
  • 财政年份:
    2011
  • 资助金额:
    $ 35.05万
  • 项目类别:
Drosophila Linker Histone H1 Functions in Chromosome Architecture and Activity
果蝇连接组蛋白 H1 在染色体结构和活性中的功能
  • 批准号:
    8043743
  • 财政年份:
    2011
  • 资助金额:
    $ 35.05万
  • 项目类别:
Drosophila Linker Histone H1 Functions in Chromosome Architecture and Activity
果蝇连接组蛋白 H1 在染色体结构和活性中的功能
  • 批准号:
    9167799
  • 财政年份:
    2011
  • 资助金额:
    $ 35.05万
  • 项目类别:

相似海外基金

Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
  • 批准号:
    MR/X02329X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.05万
  • 项目类别:
    Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
  • 批准号:
    MR/Y009568/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.05万
  • 项目类别:
    Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
  • 批准号:
    10090332
  • 财政年份:
    2024
  • 资助金额:
    $ 35.05万
  • 项目类别:
    Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
  • 批准号:
    MR/X021882/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.05万
  • 项目类别:
    Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
  • 批准号:
    2312694
  • 财政年份:
    2024
  • 资助金额:
    $ 35.05万
  • 项目类别:
    Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
  • 批准号:
    EP/Y003527/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.05万
  • 项目类别:
    Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
  • 批准号:
    EP/Y030338/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.05万
  • 项目类别:
    Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
  • 批准号:
    MR/X029557/1
  • 财政年份:
    2024
  • 资助金额:
    $ 35.05万
  • 项目类别:
    Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
  • 批准号:
    24K19395
  • 财政年份:
    2024
  • 资助金额:
    $ 35.05万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
  • 批准号:
    2244994
  • 财政年份:
    2023
  • 资助金额:
    $ 35.05万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了