RETINOIC ACID RECEPTOR IN MYELOID LEUKEMIA
髓系白血病中的视黄酸受体
基本信息
- 批准号:3199940
- 负责人:
- 金额:$ 28.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1991
- 资助国家:美国
- 起止时间:1991-07-18 至 1996-06-30
- 项目状态:已结题
- 来源:
- 关键词:Retroviridae acute myelogenous leukemia cell differentiation complementary DNA computer assisted sequence analysis gene expression gene mutation genetic regulation hematopoietic stem cells high performance liquid chromatography messenger RNA molecular cloning oncogenes polymerase chain reaction protein sequence protein structure receptor binding retinoate retinoid binding proteins steroid hormone receptor thyroid hormones transcription factor transfection
项目摘要
Retinoic acid (RA) induces the in vitro granulocytic differentiation of the
HL-60 promyelocytic leukemia cell line and is a potentially attractive
alternative therapeutic agent for the treatment of acute myelogenous
leukemia (AML) particularly of the promyelocytic (M3) variety.
Nevertheless, the therapeutic efficacy of RA is severely limited by the
fact that it does not induce differentiation of most other types of AML
cells. Utilizing retroviral-mediated gene transduction we have determined
that the retinoic acid receptor alpha (RAR-alpha), a member of the
steroid/thyroid hormone receptor superfamily of nuclear transcription
factors, plays a critical and central role in mediating RA-induced
granulocytic differentiation of HL-60 cells. Paradoxically, however, most
myeloid leukemia cells, including those that are clearly RA-unresponsive,
also express RA receptor alpha mRNA. We wish to determine whey some AML
cells are sensitive to RA-induced terminal differentiation while most
others are not. We will determine whether RA-resistant myeloid leukemias
exhibit structural and functional abnormalities in the RA receptor itself,
harbor other factors such as thyroid hormone receptors or "dominant
negative" RA receptor mutations which may negatively regulate the activity
of normal RA receptors, or exhibit differences in molecular events
occurring "downstream" of RA receptor activation. We will also assess the
tissue specific activity of the different RA receptors (RAR- alpha, beta,
gamma and RXR-alpha) in hematopoietic cells. These studies should help
determine the molecular basis for both RA-induced differentiation and RA-
resistance of myeloid leukemia cells. Moreover, the studies on thyroid
hormone-retinoic acid receptor interaction should provide considerable
insight into the role these important transcription factors play in
hematopoietic cell growth and differentiation.
维甲酸(RA)体外诱导粒细胞分化的实验研究
HL-60早幼粒细胞白血病细胞系是一种具有潜在吸引力的
治疗急性髓系白血病的替代治疗药物
白血病(AML),尤其是早幼粒细胞白血病(M3)。
然而,RA的治疗效果受到以下因素的严重限制
它不会引起大多数其他类型的急性髓细胞白血病的分化
细胞。利用逆转录病毒介导的基因转导,我们已经确定
维甲酸受体α(RAR-α)是
核转录类固醇/甲状腺激素受体超家族
因子在介导RA诱导中起着关键和核心的作用
HL-60细胞向粒细胞分化的实验研究然而,矛盾的是,大多数
髓系白血病细胞,包括那些明显对RA不敏感的细胞,
同时也表达RA受体αmRNA。我们希望确定为什么会有一些AML
细胞对RA诱导的终末分化敏感,而大多数细胞
其他人则不是。我们将确定RA耐药髓系白血病
表现出RA受体本身的结构和功能异常,
其他因素,如甲状腺激素受体或“显性”
“阴性”RA受体突变可能对活性产生负性调节
正常RA受体的差异,或者在分子事件上表现出差异
发生在RA受体激活的“下游”。我们亦会评估
不同RA受体的组织特异性活性(RAR-α,β,
γ和RXR-α)。这些研究应该会有所帮助
确定类风湿性关节炎诱导分化和类风湿关节炎的分子基础
髓系白血病细胞的耐药性。此外,对甲状腺的研究
激素-维甲酸受体的相互作用应该会提供相当大的
洞察这些重要的转录因子在
造血细胞的生长和分化。
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)
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STEVEN Collins COLLINS其他文献
STEVEN Collins COLLINS的其他文献
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{{ truncateString('STEVEN Collins COLLINS', 18)}}的其他基金
Targeting the CaM Kinase Cascade in Treating Myeloid Leukemia
靶向 CaM 激酶级联治疗髓系白血病
- 批准号:
7246550 - 财政年份:2006
- 资助金额:
$ 28.44万 - 项目类别:
Targeting the CaM Kinase Cascade in Treating Myeloid Leukemia
靶向 CaM 激酶级联治疗髓系白血病
- 批准号:
7434035 - 财政年份:2006
- 资助金额:
$ 28.44万 - 项目类别:
Targeting the CaM Kinases in Treating Myeloid Leukemia
靶向 CaM 激酶治疗髓系白血病
- 批准号:
7146498 - 财政年份:2006
- 资助金额:
$ 28.44万 - 项目类别:
Targeting the CaM Kinases in Treating Myeloid Leukemia
靶向 CaM 激酶治疗髓系白血病
- 批准号:
7626246 - 财政年份:2006
- 资助金额:
$ 28.44万 - 项目类别:
RA RECEPTOR REGULATION ON HEMATOPOIETIC STEM CELLS
RA 受体对造血干细胞的调节
- 批准号:
6652839 - 财政年份:2002
- 资助金额:
$ 28.44万 - 项目类别:
RA RECEPTOR REGULATION ON HEMATOPOIETIC STEM CELLS
RA 受体对造血干细胞的调节
- 批准号:
6494847 - 财政年份:2001
- 资助金额:
$ 28.44万 - 项目类别:
RA RECEPTOR REGULATION ON HEMATOPOIETIC STEM CELLS
RA 受体对造血干细胞的调节
- 批准号:
6358968 - 财政年份:2000
- 资助金额:
$ 28.44万 - 项目类别:
HEMOPOIETIC STEM CELL SELF RENEWAL AND RETINOID ANTAGONISTS
造血干细胞自我更新和类维生素A拮抗剂
- 批准号:
6202419 - 财政年份:1999
- 资助金额:
$ 28.44万 - 项目类别:
HEMOPOIETIC STEM CELL SELF RENEWAL AND RETINOID ANTAGONISTS
造血干细胞自我更新和类维生素A拮抗剂
- 批准号:
6110531 - 财政年份:1998
- 资助金额:
$ 28.44万 - 项目类别:
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