Converting an Oncogene to an Apoptotic Factor by Manipulating Signal Sequences

通过操纵信号序列将癌基因转化为凋亡因子

基本信息

  • 批准号:
    7758311
  • 负责人:
  • 金额:
    $ 28.37万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-04-01 至 2013-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Changing the subcellular localization of a signal transducing protein involved in disease is a novel approach for therapeutic intervention. The subcellular location of some proteins plays a critical role in the etiology of disease. A precise example of this is Bcr- Abl protein, the causative agent of chronic myelogenous leukemia (CML). When Bcr-Abl is in the cytoplasm of cells, it behaves as an oncogene, but if forced to the nucleus, it becomes an apoptotic factor. CML is a myeloproliferative disorder characterized by increased proliferation of granulocytes and their immature precursors; with a median survival time of 4 to 6 years. The goal of this study is to use our ligand responsive protein switch constructs to control the subcellular location of Bcr-Abl, and convert Bcr- Abl from an oncogene to an apoptotic factor. It has been shown that depletion of Bcr- Abl from the cytoplasm by nuclear trapping of Bcr-Abl can result in apoptosis. If Bcr-Abl can be directed to the nucleus, it can be converted from an oncogene to an apoptotic factor. Since Bcr-Abl oligomerizes with itself to form tetramers, nuclear trapping could be achieved by introducing exogenously localization-controllable Bcr-Abl. Upon ligand induction, localization controllable Bcr-Abl will oligomerize with wt Bcr-Abl and will undergo transport to the nucleus, followed by cellular apoptosis. In Aim 1 we will subclone localization controllable versions of Bcr-Abl (Bcr-Abl protein switch, PS) with a fluorescent tag and show oligomerization with wild-type (wt) Bcr-Abl, translocate to the nucleus, and cause apoptosis of Bcr-Abl positive K562 cells. Localization of Bcr-Abl PS will be monitored by fluorescence microscopy, and apoptosis will be tested using standard cell death assays. Interaction of wt Bcr-Abl with Bcr-Abl PS will be determined using an in vivo oligomerization between wt Bcr-Abl and Bcr-Abl protein switch and mammalian two-hybrid assay. Aim 2 will test the Bcr-Abl PS in Gleevec.-resistant leukemic cells similarly. Aim 3 will test and use specific promoters that allow preferential expression of Bcr-Abl PS in leukemia cells only. Aim 4 will test if Bcr-Abl PS will eradicate/diminish leukemia in a human xenograft model using Balb/C nude mice injected with human leukemia cells. Our goal is to use ligand responsive protein switch constructs to control the subcellular location of Bcr-Abl, and convert Bcr-Abl from an oncogene to an apoptotic factor. Our long-term, ultimate goal is to use localization controllable versions of Bcr-Abl (as gene therapy) for treatment of CML.
描述(申请人提供):改变与疾病有关的信号转导蛋白的亚细胞定位是治疗干预的一种新方法。某些蛋白质的亚细胞定位在疾病的病因学中起着关键作用。一个确切的例子是bcr-Abl蛋白,它是慢性粒细胞白血病(CML)的病原体。当bcr-Abl在细胞质中时,它表现为癌基因,但如果被迫进入细胞核,它就会成为一种凋亡因子。CML是一种骨髓增生性疾病,以粒细胞及其未成熟前体细胞增殖增加为特征,中位生存期为4-6年。这项研究的目的是利用我们的配体反应蛋白开关结构来控制bcr-Abl的亚细胞位置,并将bcr-abl从癌基因转化为凋亡因子。已有研究表明,通过BCR-Abl的核捕获使bcr-Abl从细胞质中耗尽,可导致细胞凋亡。如果bcr-Abl能够被定向到细胞核,它就可以从癌基因转化为凋亡因子。由于bcr-Abl与自身齐聚形成四聚体,因此可以通过引入外源定位可控的bcr-abl来实现核捕获。在配体诱导下,定位可控的bcr-Abl将与wt bcr-abl齐聚,并转运到细胞核,随后发生细胞凋亡。在目标1中,我们将用荧光标记亚克隆定位可控的bcr-abl(bcr-abl蛋白开关,PS),并与野生型(Wt)bcr-abl发生寡聚,转位到细胞核,并诱导bcr-abl阳性的K562细胞凋亡。Bcr-abl PS的定位将通过荧光显微镜进行监测,凋亡将使用标准的细胞死亡分析进行测试。Wt bcr-Abl和bcr-abl蛋白开关的体内齐聚和哺乳动物双杂交实验将确定wt bcr-Abl与bcr-abl PS的相互作用。Aim 2将类似地在格列卫耐药的白血病细胞中测试bcr-abl PS。AIM 3将测试和使用仅允许bcr-abl PS在白血病细胞中优先表达的特定启动子。Aim 4将测试BCR-Abl PS能否在人异种移植模型中根除/减少白血病,该模型使用注入人白血病细胞的Balb/C裸鼠。我们的目标是使用配体反应蛋白开关结构来控制bcr-Abl的亚细胞位置,并将bcr-abl从癌基因转化为凋亡因子。我们的长期、最终目标是使用定位可控版本的bcr-abl(作为基因治疗)来治疗CML。

项目成果

期刊论文数量(0)
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Carol S. Lim其他文献

MULTI-DOMAIN TARGETING OF BCR-ABL BY DISRUPTION OF OLIGOMERIZATION AND TYROSINE KINASE INHIBITION: TOWARDS ERADICATION OF CML
通过破坏寡聚化和抑制酪氨酸激酶来靶向 BCR-ABL 的多域:走向根除 CML
  • DOI:
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Geoffrey D. Miller;David W. Woessner;M. Sirch;Carol S. Lim
  • 通讯作者:
    Carol S. Lim
Model system to study classical nuclear export signals
研究经典核输出信号的模型系统
  • DOI:
    10.1208/ps040318
  • 发表时间:
    2008
  • 期刊:
  • 影响因子:
    0
  • 作者:
    C. Kanwal;Henan Li;Carol S. Lim
  • 通讯作者:
    Carol S. Lim
Organelle-specific targeting in drug delivery and design
  • DOI:
    10.1016/j.addr.2007.06.001
  • 发表时间:
    2007-08
  • 期刊:
  • 影响因子:
    16.1
  • 作者:
    Carol S. Lim
  • 通讯作者:
    Carol S. Lim
Development of an Effective Therapy for CML
开发 CML 有效疗法
  • DOI:
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    0
  • 作者:
    David W. Woessner;Carol S. Lim;M. Deininger
  • 通讯作者:
    M. Deininger
Simultaneous Visualization of the Yellow and Green Forms of the Green Fluorescent Protein in Living Cells
同时观察活细胞中绿色荧光蛋白的黄色和绿色形式

Carol S. Lim的其他文献

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{{ truncateString('Carol S. Lim', 18)}}的其他基金

A Leukemia Cell-Specific Coiled-Coil Protein for Treatment of Chronic Myeloid Leukemia
用于治疗慢性粒细胞白血病的白血病细胞特异性卷曲螺旋蛋白
  • 批准号:
    10319608
  • 财政年份:
    2021
  • 资助金额:
    $ 28.37万
  • 项目类别:
Re-engineered Mitochondrially Targeted p53 Gene Therapy in Liver Cancer
重新设计的线粒体靶向 p53 基因疗法治疗肝癌
  • 批准号:
    10317129
  • 财政年份:
    2021
  • 资助金额:
    $ 28.37万
  • 项目类别:
A Leukemia Cell-Specific Coiled-Coil Protein for Treatment of Chronic Myeloid Leukemia
用于治疗慢性粒细胞白血病的白血病细胞特异性卷曲螺旋蛋白
  • 批准号:
    10543539
  • 财政年份:
    2021
  • 资助金额:
    $ 28.37万
  • 项目类别:
Mitochondrially Targeted p53 DBD for Treatment of Ovarian Cancer
线粒体靶向 p53 DBD 治疗卵巢癌
  • 批准号:
    8957167
  • 财政年份:
    2015
  • 资助金额:
    $ 28.37万
  • 项目类别:
Simultaneous Targeting of p53 to the Nucleus and Mitochondria for Cancer Therapy
p53 同时靶向细胞核和线粒体用于癌症治疗
  • 批准号:
    8274895
  • 财政年份:
    2010
  • 资助金额:
    $ 28.37万
  • 项目类别:
Simultaneous Targeting of p53 to the Nucleus and Mitochondria for Cancer Therapy
p53 同时靶向细胞核和线粒体用于癌症治疗
  • 批准号:
    8467689
  • 财政年份:
    2010
  • 资助金额:
    $ 28.37万
  • 项目类别:
Simultaneous Targeting of p53 to the Nucleus and Mitochondria for Cancer Therapy
p53 同时靶向细胞核和线粒体用于癌症治疗
  • 批准号:
    8100507
  • 财政年份:
    2010
  • 资助金额:
    $ 28.37万
  • 项目类别:
Converting an Oncogene to an Apoptotic Factor by Manipulating Signal Sequences
通过操纵信号序列将癌基因转化为凋亡因子
  • 批准号:
    7388044
  • 财政年份:
    2008
  • 资助金额:
    $ 28.37万
  • 项目类别:
Converting an Oncogene to an Apoptotic Factor by Manipulating Signal Sequences
通过操纵信号序列将癌基因转化为凋亡因子
  • 批准号:
    8212586
  • 财政年份:
    2008
  • 资助金额:
    $ 28.37万
  • 项目类别:
Converting an Oncogene to an Apoptotic Factor by Manipulating Signal Sequences
通过操纵信号序列将癌基因转化为凋亡因子
  • 批准号:
    7588848
  • 财政年份:
    2008
  • 资助金额:
    $ 28.37万
  • 项目类别:

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