IEX-1 as a potential biomarker for early detection of myelodysplastic syndromes

IEX-1 作为早期检测骨髓增生异常综合征的潜在生物标志物

基本信息

  • 批准号:
    8311631
  • 负责人:
  • 金额:
    $ 17.24万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-09-01 至 2014-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this proposal is to determine a potential of IEX-1 (Immediate Early responsive gene X-1) as a biomarker for the early diagnosis of myelodysplastic syndromes (MDS) or its progression to acute myeloid leukemia (AML). MDS is a clonal disorder of hematopoietic stem cells (HSCs) presumably resulting from the accumulation of mutations in genes that control the differentiation, self-renewal, or proliferation of HSCs. An unusual high frequency of genetic alterations in HSCs in MDS patients may be ascribed in part to increased production of reactive oxygen species (ROS) that causes DNA mutations, which could in turn lead to acquisition of additional genomic changes and ROS formation. IEX-1 takes part in regulating a balance between ROS generation and oxidative phosphorylation in mitochondria by targeting the inhibitor of mitochondrial FoF1-ATP synthase (IF1) to degradation. Over-expression of IEX-1 reduced the level of IF1 expression, concomitant with diminished ROS production, protecting cells from mitochondrion-dependent apoptosis. On the contrary, null mutation of IEX-1 stabilized IF1 expression and increased the susceptibility of cells to apoptosis. In accordance with a role of IEX-1 in the survival and differentiation of HSCs, IEX-1 deficient HSCs exhibited a high rate of apoptosis and proliferation but a decrease in their generation. Moreover, several studies recently showed that IEX-1 expression was deregulated in more than half of patients with MDS and the deregulation was correlated with the progression of the disease and the apoptosis level in CD34+ stem cells in the patients. Based on these observations, we hypothesize that deregulation of IEX-1 expression contributes significantly to the development of MDS and its progression to AML. We will test this hypothesis by long term competitive repopulation assays so as to determine whether or how IEX-1 contributes to MDS development via an autonomous or extrinsic fashion. The reconstituted mice will be then treated with anti-oxidant to restore the self-renewal capacity of HSCs. In aim 2, we will expose IEX-1 knockout (KO) mice to radiation or chemotherapy that offers a "second hit", rendering them more susceptible to radiation- or chemotherapy-induced DNA mutations and thus MDS/AML development. An increase in the susceptibility of IEX-1 KO mice to MDS/AML after the treatment will suggest that IEX-1 is one of the "multiple hits" causing the genomic instability in HSCs and can be thus used as a biomarker for the prognosis of myeloid disorders. The study may also provide new insights into the mechanism for the disease development and help to develop novel strategies to prevent it.
描述(由申请人提供):本提案的总体目标是确定IEX-1(即早反应基因X-1)作为早期诊断骨髓增生异常综合征(MDS)或其进展为急性髓性白血病(AML)的生物标志物的潜力。MDS是造血干细胞(HSC)的克隆性疾病,推测是由控制HSC分化、自我更新或增殖的基因突变积累引起的。MDS患者HSC中异常高频率的遗传改变可能部分归因于导致DNA突变的活性氧(ROS)产生增加,这反过来可能导致获得额外的基因组变化和ROS形成。IEX-1通过靶向降解线粒体FoF 1-ATP合酶(IF 1)抑制剂参与调节线粒体中ROS产生和氧化磷酸化之间的平衡。IEX-1的过表达降低了IF 1的表达水平,同时减少了ROS的产生,保护细胞免受依赖于细胞凋亡的损伤。相反,IEX-1的无效突变稳定了IF 1的表达并增加了细胞对凋亡的易感性。根据IEX-1在HSC存活和分化中的作用,IEX-1缺陷的HSC表现出高的凋亡和增殖率,但其生成减少。此外,最近的一些研究表明,IEX-1的表达失调,在超过一半的MDS患者和失调与疾病的进展和患者的CD 34+干细胞的凋亡水平。基于这些观察,我们假设IEX-1表达的失调显著促进MDS的发展及其向AML的进展。我们将通过长期竞争性再增殖试验来检验这一假设,以确定IEX-1是否或如何通过自主或外在方式促进MDS的发展。然后用抗氧化剂处理重建的小鼠以恢复HSC的自我更新能力。在目标2中,我们将IEX-1敲除(KO)小鼠暴露于放射或化疗,提供“第二次打击”,使它们更容易受到放射或化疗诱导的DNA突变,从而导致MDS/AML的发展。治疗后IEX-1 KO小鼠对MDS/AML的易感性增加将表明IEX-1是导致HSC中基因组不稳定性的“多次命中”之一,因此可用作骨髓疾病预后的生物标志物。该研究还可能为疾病发展机制提供新的见解,并有助于开发新的预防策略。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mitoquinone restores platelet production in irradiation-induced thrombocytopenia.
  • DOI:
    10.3109/09537104.2014.935315
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    Ramsey H;Zhang Q;Wu MX
  • 通讯作者:
    Wu MX
Mitochondrial anti-oxidant protects IEX-1 deficient mice from organ damage during endotoxemia.
线粒体抗氧化剂可保护IEX-1缺乏的小鼠免受内毒素血症期间器官损伤。
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Mei X Wu其他文献

Mei X Wu的其他文献

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{{ truncateString('Mei X Wu', 18)}}的其他基金

A new mucosal adjuvant for augmenting influenza vaccines in elderly
一种用于增强老年人流感疫苗接种效果的新型粘膜佐剂
  • 批准号:
    10409833
  • 财政年份:
    2021
  • 资助金额:
    $ 17.24万
  • 项目类别:
A new mucosal adjuvant for augmenting influenza vaccines in elderly
一种用于增强老年人流感疫苗接种效果的新型粘膜佐剂
  • 批准号:
    10304406
  • 财政年份:
    2021
  • 资助金额:
    $ 17.24万
  • 项目类别:
Delivery of Powdered Vaccines for Improving Newborn Vaccination
提供粉状疫苗以改善新生儿疫苗接种
  • 批准号:
    10092941
  • 财政年份:
    2020
  • 资助金额:
    $ 17.24万
  • 项目类别:
Biomimetic nanoparticles to enhance the breadth of influenza vaccines
仿生纳米颗粒可增强流感疫苗的广度
  • 批准号:
    10455053
  • 财政年份:
    2020
  • 资助金额:
    $ 17.24万
  • 项目类别:
Sample-free onsite detection of cocaine using microneedles via laser-treated skin
使用微针通过激光处理的皮肤对可卡因进行无样品现场检测
  • 批准号:
    9044652
  • 财政年份:
    2016
  • 资助金额:
    $ 17.24万
  • 项目类别:
Laser-facilitated powder-allergen delivery for epicutaneous immunotherapy
用于表皮免疫治疗的激光促进粉末过敏原递送
  • 批准号:
    8892996
  • 财政年份:
    2014
  • 资助金额:
    $ 17.24万
  • 项目类别:
Laser-facilitated powder-allergen delivery for epicutaneous immunotherapy
用于表皮免疫治疗的激光促进粉末过敏原递送
  • 批准号:
    8770696
  • 财政年份:
    2014
  • 资助金额:
    $ 17.24万
  • 项目类别:
Laser-facilitated delivery of malarial sporozoites from the skin to liver
激光促进疟疾子孢子从皮肤输送至肝脏
  • 批准号:
    8495256
  • 财政年份:
    2012
  • 资助金额:
    $ 17.24万
  • 项目类别:
Laser-facilitated delivery of malarial sporozoites from the skin to liver
激光促进疟疾子孢子从皮肤输送至肝脏
  • 批准号:
    8385605
  • 财政年份:
    2012
  • 资助金额:
    $ 17.24万
  • 项目类别:
Boosting Flu Vaccination without Adjuvant Injection
无需注射佐剂即可加强流感疫苗接种
  • 批准号:
    8263742
  • 财政年份:
    2011
  • 资助金额:
    $ 17.24万
  • 项目类别:

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