ROLE OF THE CHROMATIN REGULATOR, MLL, IN T CELL DEVELOPMENT

染色质调节因子 MLL 在 T 细胞发育中的作用

基本信息

  • 批准号:
    7959994
  • 负责人:
  • 金额:
    $ 8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-07-01 至 2010-06-30
  • 项目状态:
    已结题

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. My group aims to understand the normal function of the MLL proto-oncogene particularly during the development and function of the hematopoietic system. The MLL gene encodes a large nuclear chromatin regulator that is disrupted in common chromosomal translocations found in leukemia. To study the normal role of MLL during hematopoiesis, we have developed a loxP-flanked allele of the murine Mll gene, backcrossed this strain and crossed these animals to either inducible or lineage-specific Cre recombinase mouse strains. This approach allowed us to study the effect of Mll loss on multiple hematopoietic cell types during adult steady state hematopoiesis. Using this model, we demonstrated that the maintenance of hematopoietic stem and progenitor populations absolutely depends on Mll. We demonstrated that this was likely due to two different cell-context dependent roles of Mll in these primitive cell types. First, Mll deletion in hematopoietic stem cells resulted in their escape from quiescence and an increase in proliferation, coupled to symmetric differentiation of progeny cells. This resulted in the rapid exhaustion of stem cell activity from the bone marrow. Second, we demonstrated that in myelo-erythroid progenitors, Mll deficiency resulted in the reduction in proliferation resulting in reduced progenitor pool sizes. Together, these alterations resulted in the rapid decline in bone marrow cell numbers upon Mll deletion and ultimately bone marrow failure and animal death. Surprisingly, when we crossed the Mll loxP flanked strain to Cre transgenic animals that express Cre only in differentiating lineages (T cells [lck-Cre], B cells [CD19-Cre] or myelomonocytic precursors [lysozyme M-Cre]), we found that there was no effect on steady state cell numbers, demonstrating that Mll is only essential in the early stem and progenitor populations. In the current proposal, we focused on a potential independent MLL function in T cell activation, as we had demonstrated a biochemical collaboration between domains within MLL and the sequence-specific activator CREB, which is known to function in T cell activation.
这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金, 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我的团队旨在了解MLL原癌基因的正常功能,特别是在造血系统的发育和功能过程中。MLL基因编码一种大的核染色质调节因子,在白血病常见的染色体易位中被破坏。为了研究MLL在造血过程中的正常作用,我们开发了小鼠MLL基因的loxP侧翼等位基因,回交该品系,并将这些动物与可诱导的或谱系特异性的Cre重组酶小鼠品系杂交。这种方法使我们能够研究MLL丢失对成人稳态造血过程中多种造血细胞类型的影响。利用这一模型,我们证明了造血干/祖细胞群的维持完全依赖于MLL。我们证明,这可能是由于MLL在这些原始细胞类型中的两个不同的细胞上下文依赖角色。首先,造血干细胞中MLL的缺失导致它们摆脱静止状态,增加增殖,并伴随着子代细胞的对称分化。这导致了骨髓中干细胞活性的迅速耗尽。第二,我们证明在骨髓红系祖细胞中,MLL缺乏导致增殖减少,导致祖细胞池大小减小。总之,这些改变导致MLL缺失后骨髓细胞数量迅速下降,最终导致骨髓衰竭和动物死亡。令人惊讶的是,当我们将MLL loxP侧翼株与仅在分化谱系(T细胞[Lck-Cre]、B细胞[CD19-Cre]或骨髓单核细胞前体[Lysozyme M-Cre])中表达Cre的转基因动物杂交时,我们发现对稳定状态的细胞数量没有影响,表明MLL只在早期干祖细胞群中是必需的。在目前的方案中,我们将重点放在T细胞激活中潜在的独立MLL功能上,因为我们已经证明了MLL中的结构域与序列特异性激活剂CREB之间的生化协作,CREB已知在T细胞激活中发挥作用。

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)

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 }}

Patricia Ernst其他文献

Patricia Ernst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('Patricia Ernst', 18)}}的其他基金

Escape from CAR T surveillance through lineage plasticity
通过谱系可塑性逃避 CAR T 监控
  • 批准号:
    10419173
  • 财政年份:
    2022
  • 资助金额:
    $ 8万
  • 项目类别:
Escape from CAR T surveillance through lineage plasticity
通过谱系可塑性逃避 CAR T 监控
  • 批准号:
    10581656
  • 财政年份:
    2022
  • 资助金额:
    $ 8万
  • 项目类别:
Enhancing hematopoiesis through modulation of a histone methyltransferase: evaluating a new MLL1 gain-of-function animal model
通过调节组蛋白甲基转移酶增强造血功能:评估新的 MLL1 功能获得动物模型
  • 批准号:
    9814577
  • 财政年份:
    2019
  • 资助金额:
    $ 8万
  • 项目类别:
Enhancing hematopoiesis through modulation of a histone methyltransferase: evaluating a new MLL1 gain-of-function animal model
通过调节组蛋白甲基转移酶增强造血功能:评估新的 MLL1 功能获得动物模型
  • 批准号:
    10212374
  • 财政年份:
    2019
  • 资助金额:
    $ 8万
  • 项目类别:
Enhancing hematopoiesis through modulation of a histone methyltransferase: evaluating a new MLL1 gain-of-function animal model
通过调节组蛋白甲基转移酶增强造血功能:评估新的 MLL1 功能获得动物模型
  • 批准号:
    10017193
  • 财政年份:
    2019
  • 资助金额:
    $ 8万
  • 项目类别:
MLL Family Histone Methyltransferases in Myeloid Leukemia
髓系白血病中的 MLL 家族组蛋白甲基转移酶
  • 批准号:
    10406930
  • 财政年份:
    2018
  • 资助金额:
    $ 8万
  • 项目类别:
Modeling hematologic malignancy and self-renewal with gain-of-function MLL1
利用功能获得 MLL1 模拟血液恶性肿瘤和自我更新
  • 批准号:
    8974958
  • 财政年份:
    2014
  • 资助金额:
    $ 8万
  • 项目类别:
MLL Function in the Maintenance of the Blood Forming System
MLL 在维持造血系统中的功能
  • 批准号:
    8974685
  • 财政年份:
    2014
  • 资助金额:
    $ 8万
  • 项目类别:
MLL Function in the Maintenance of the Blood Forming System
MLL 在维持造血系统中的功能
  • 批准号:
    7867478
  • 财政年份:
    2009
  • 资助金额:
    $ 8万
  • 项目类别:
ROLE OF THE CHROMATIN REGULATOR, MLL, IN T CELL DEVELOPMENT
染色质调节因子 MLL 在 T 细胞发育中的作用
  • 批准号:
    7720751
  • 财政年份:
    2008
  • 资助金额:
    $ 8万
  • 项目类别:

相似海外基金

Linkage of HIV amino acid variants to protective host alleles at CHD1L and HLA class I loci in an African population
非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
  • 批准号:
    502556
  • 财政年份:
    2024
  • 资助金额:
    $ 8万
  • 项目类别:
Olfactory Epithelium Responses to Human APOE Alleles
嗅觉上皮对人类 APOE 等位基因的反应
  • 批准号:
    10659303
  • 财政年份:
    2023
  • 资助金额:
    $ 8万
  • 项目类别:
Deeply analyzing MHC class I-restricted peptide presentation mechanistics across alleles, pathways, and disease coupled with TCR discovery/characterization
深入分析跨等位基因、通路和疾病的 MHC I 类限制性肽呈递机制以及 TCR 发现/表征
  • 批准号:
    10674405
  • 财政年份:
    2023
  • 资助金额:
    $ 8万
  • 项目类别:
An off-the-shelf tumor cell vaccine with HLA-matching alleles for the personalized treatment of advanced solid tumors
具有 HLA 匹配等位基因的现成肿瘤细胞疫苗,用于晚期实体瘤的个性化治疗
  • 批准号:
    10758772
  • 财政年份:
    2023
  • 资助金额:
    $ 8万
  • 项目类别:
Identifying genetic variants that modify the effect size of ApoE alleles on late-onset Alzheimer's disease risk
识别改变 ApoE 等位基因对迟发性阿尔茨海默病风险影响大小的遗传变异
  • 批准号:
    10676499
  • 财政年份:
    2023
  • 资助金额:
    $ 8万
  • 项目类别:
New statistical approaches to mapping the functional impact of HLA alleles in multimodal complex disease datasets
绘制多模式复杂疾病数据集中 HLA 等位基因功能影响的新统计方法
  • 批准号:
    2748611
  • 财政年份:
    2022
  • 资助金额:
    $ 8万
  • 项目类别:
    Studentship
Recessive lethal alleles linked to seed abortion and their effect on fruit development in blueberries
与种子败育相关的隐性致死等位基因及其对蓝莓果实发育的影响
  • 批准号:
    22K05630
  • 财政年份:
    2022
  • 资助金额:
    $ 8万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles
诱导多能干细胞的基因组和表观基因组编辑用于研究骨关节炎风险等位基因
  • 批准号:
    10532032
  • 财政年份:
    2022
  • 资助金额:
    $ 8万
  • 项目类别:
Investigating the Effect of APOE Alleles on Neuro-Immunity of Human Brain Borders in Normal Aging and Alzheimer's Disease Using Single-Cell Multi-Omics and In Vitro Organoids
使用单细胞多组学和体外类器官研究 APOE 等位基因对正常衰老和阿尔茨海默病中人脑边界神经免疫的影响
  • 批准号:
    10525070
  • 财政年份:
    2022
  • 资助金额:
    $ 8万
  • 项目类别:
Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians
利用进化历史来改进夏威夷原住民性状相关等位基因的识别和风险分层模型
  • 批准号:
    10689017
  • 财政年份:
    2022
  • 资助金额:
    $ 8万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了