Study DNA repair in preventing MDS and AML after radiation and benzene exposure

研究 DNA 修复在辐射和苯暴露后预防 MDS 和 AML 的作用

基本信息

项目摘要

DESCRIPTION (provided by applicant): Myelodysplastic syndrome (MDS) is a group of disorders characterized by dysfunctional blood cells that can progress to acute myeloid leukemia (AML). At this time the etiology of MDS development and progression to AML is not understood and there is no cure (median survival at time of diagnosis is less than 5 years). Yet, DNA damage and mutations appear to play a key role with the initiating defect in a hematopoietic stem cell (HSC). In support, people with certain DNA repair defective syndromes including Fanconi anemia (FA) and Bloom syndrome (BS) exhibit MDS. Interestingly, FA and BS are mechanistically related since the BS protein associates with proteins in the FA pathway and since both influence the repair of DNA double-strand breaks (DSBs) through the homologous recombination (HR) pathway. In addition, some DNA damaging agents appear to predispose people to MDS/AML including ?-radiation and benzene. Both of these agents cause chromosomal abnormalities and HR repairs ?-radiation-induced DSBs. Furthermore, another DSB repair pathway, nonhomologous end joining (NHEJ) may enable the progression of MDS/AML by facilitating chromosomal translocations. Thus, DNA damage and DNA repair appear to be integral factors in the etiology of MDS/AML. This proposal is a collaboration between two labs with expertise in MDS/AML, (Dr. Rebel's lab) and DNA damage/repair (Dr. Hasty's lab). Dr. Rebel has studied MDS/AML in a Crebbp-deficient mouse model. Crebbp is a transcriptional coactivator and Crebbp-deficient mice invariably develop MDS with age that often progress to AML. Importantly, these mice are defective for repairing ?-radiation-induced DNA breaks and exhibit elevated mutation levels in fetal liver cells. Thus, Dr. Rebel's analysis on Crebbp-deficient mice support observations made on patients that DNA damage and defects in DNA repair are causal factors in MDS/AML. Therefore, the hypothesis is that fully functional HR is critical for suppressing MDS/AML in response to genotoxins that cause DSBs while NHEJ generates chromosomal translocations that cause MDS/AML. Two specific aims are presented to address the hypothesis. Crebbp-deficient mouse embryonic stem (ES) cells (Specific Aim 1) and mice (aim 2) will be investigated for the dynamics of repairing ?-radiation- and benzene-induced DNA lesions and the development of MDS and progression to AML. It is anticipated that this will lead to a better understanding of the role that DNA damage/repair plays in disease progression, the impact these genotoxins have on a variety of bone marrow cells including HSCs and vulnerable times of exposure (embryonic development vs. adult). Thus, results from this proposal will elucidate the pathobiology of MDS/AML. PUBLIC HEALTH RELEVANCE: Myelodysplastic syndrome (MDS) is a pre-leukemic bone marrow disorder that may progress to acute myeloid leukemia (AML). Genetic instability likely facilitates each stage of this disease with the initiating event occurring in a HSC; therefore, environmental genotoxins and defective DNA repair that are known to cause genetic instability could enable MDS/AML. The goal of this proposal is to elucidate the role DNA repair and genomic instability play in the etiology of this poorly understood disease.
描述(由申请人提供):骨髓增生异常综合征(MDS)是一组以血细胞功能障碍为特征的疾病,可进展为急性髓性白血病(AML)。目前,MDS发展和进展为AML的病因尚不清楚,也无法治愈(诊断时的中位生存期小于5年)。然而,DNA损伤和突变似乎在造血干细胞(HSC)中的起始缺陷中起关键作用。作为支持,患有某些DNA修复缺陷综合征(包括范可尼贫血(FA)和布鲁姆综合征(BS))的人表现出MDS。有趣的是,FA和BS是机械相关的,因为BS蛋白与FA途径中的蛋白质相关联,并且因为两者都通过同源重组(HR)途径影响DNA双链断裂(DSB)的修复。此外,一些DNA损伤剂似乎使人易患MDS/AML,包括?辐射和苯。这两种药物都会导致染色体异常和HR修复?辐射诱发的DSB。此外,另一种DSB修复途径,非同源末端连接(NHEJ)可能通过促进染色体易位而使MDS/AML进展。因此,DNA损伤和DNA修复似乎是骨髓增生异常综合征/急性粒细胞白血病病因中不可或缺的因素。该提案是两个在MDS/AML(Rebel博士的实验室)和DNA损伤/修复(Hasty博士的实验室)方面拥有专业知识的实验室之间的合作。Rebel博士在Crebbp缺陷小鼠模型中研究了MDS/AML。Crebbp是一种转录辅激活因子,Crebbp缺陷小鼠总是随着年龄的增长而发展为MDS,通常进展为AML。重要的是,这些老鼠有修复缺陷吗?辐射诱导的DNA断裂并在胎儿肝细胞中表现出升高的突变水平。因此,Rebel博士对Crebbp缺陷小鼠的分析支持了对患者的观察,即DNA损伤和DNA修复缺陷是MDS/AML的致病因素。因此,假设全功能HR对于抑制MDS/AML是至关重要的,以响应导致DSB的遗传毒素,而NHEJ产生导致MDS/AML的染色体易位。两个具体的目标是解决的假设。将研究Crebbp缺陷小鼠胚胎干细胞(ES细胞)(特异性目标1)和小鼠(目标2)修复?辐射和苯诱导的DNA损伤以及MDS的发展和向AML的进展。预计这将有助于更好地了解DNA损伤/修复在疾病进展中的作用,这些遗传毒素对各种骨髓细胞(包括HSC)的影响以及暴露的脆弱时间(胚胎发育与成人)。因此,本提案的结果将阐明MDS/AML的病理生物学。 公共卫生相关性:骨髓增生异常综合征(MDS)是一种白血病前期骨髓疾病,可能进展为急性髓性白血病(AML)。遗传不稳定性可能会促进这种疾病的每个阶段,起始事件发生在HSC中;因此,已知会导致遗传不稳定性的环境遗传毒素和缺陷DNA修复可能会导致MDS/AML。该提案的目标是阐明DNA修复和基因组不稳定性在这种知之甚少的疾病病因学中的作用。

项目成果

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EDWARD PAUL HASTY其他文献

EDWARD PAUL HASTY的其他文献

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{{ truncateString('EDWARD PAUL HASTY', 18)}}的其他基金

How does TREX2 maintain and alter chromosomes?
TREX2如何维持和改变染色体?
  • 批准号:
    8925829
  • 财政年份:
    2014
  • 资助金额:
    $ 33.44万
  • 项目类别:
How does TREX2 maintain and alter chromosomes?
TREX2如何维持和改变染色体?
  • 批准号:
    8758039
  • 财政年份:
    2014
  • 资助金额:
    $ 33.44万
  • 项目类别:
Study DNA repair in preventing MDS and AML after radiation and benzene exposure
研究 DNA 修复在辐射和苯暴露后预防 MDS 和 AML 的作用
  • 批准号:
    8536292
  • 财政年份:
    2012
  • 资助金额:
    $ 33.44万
  • 项目类别:
Study DNA repair in preventing MDS and AML after radiation and benzene exposure
研究 DNA 修复在辐射和苯暴露后预防 MDS 和 AML 的作用
  • 批准号:
    8681445
  • 财政年份:
    2012
  • 资助金额:
    $ 33.44万
  • 项目类别:
Discovering TREX1 and TREX2 Function in Mammalian Cells and Mice
发现哺乳动物细胞和小鼠中的 TREX1 和 TREX2 功能
  • 批准号:
    7754073
  • 财政年份:
    2007
  • 资助金额:
    $ 33.44万
  • 项目类别:
Discovering TREX1 and TREX2 Function in Mammalian Cells and Mice
发现哺乳动物细胞和小鼠中的 TREX1 和 TREX2 功能
  • 批准号:
    7382540
  • 财政年份:
    2007
  • 资助金额:
    $ 33.44万
  • 项目类别:
Discovering TREX1 and TREX2 Function in Mammalian Cells and Mice
发现哺乳动物细胞和小鼠中的 TREX1 和 TREX2 功能
  • 批准号:
    7548181
  • 财政年份:
    2007
  • 资助金额:
    $ 33.44万
  • 项目类别:
Discovering TREX1 and TREX2 Function in Mammalian Cells and Mice
发现哺乳动物细胞和小鼠中的 TREX1 和 TREX2 功能
  • 批准号:
    8015359
  • 财政年份:
    2007
  • 资助金额:
    $ 33.44万
  • 项目类别:
Transgenic Animal and Morphology Core
转基因动物和形态学核心
  • 批准号:
    7508969
  • 财政年份:
    2007
  • 资助金额:
    $ 33.44万
  • 项目类别:
Discovering TREX1 and TREX2 Function in Mammalian Cells and Mice
发现哺乳动物细胞和小鼠中的 TREX1 和 TREX2 功能
  • 批准号:
    7263286
  • 财政年份:
    2007
  • 资助金额:
    $ 33.44万
  • 项目类别:

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