(PQ5) Mitochondria in Leukemic Stem Cell Disease Progression
(PQ5) 白血病干细胞疾病进展中的线粒体
基本信息
- 批准号:9753161
- 负责人:
- 金额:$ 37.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressBloodCell CompartmentationCell MaintenanceDataDiseaseDisease ProgressionDoxycyclineDrug resistanceDysmyelopoietic SyndromesEpigenetic ProcessEventExhibitsFOXO3A geneFailureFlow CytometryGenerationsGeneticGenetic TranscriptionGoalsHealthHematologic NeoplasmsHematopoieticHematopoietic stem cellsHeterogeneityLaboratoriesLeukemic CellMaintenanceMatrix MetalloproteinasesMetabolicMetabolismMitochondriaModelingModificationMolecularMyeloproliferative diseasePathway interactionsPhenotypePlayPopulationProcessPropertyRegulationRelapseStem cellsTestingTransgenic Micebasecancer stem cellconventional therapydesignimprovedleukemialeukemic stem cellmitochondrial metabolismmortalitymouse modelnoveloff-label usepreventstem cell biologystem-like cellsuccesstargeted treatmenttherapy resistanttranscription factortranscriptome
项目摘要
ABSTRACT
Conventional and targeted therapies have had little success in eradicating myeloid malignancies
including in myeloproliferative neoplasms (MPNs). The inability to reliably prevent the generation of a small
subset of drug-resistant stem cell-like leukemic cells (or leukemic stem cells (LSCs)) that cause relapse and
the incapacity to target LSC has contributed to this failure. Mitochondrial metabolism has been implicated in
regulating both LSC and hematopoietic stem cells (HSC) activity, however many other aspects of
mitochondrial functions that contribute to the health of stem cell machinery remain largely unknown. We
have discovered mitochondrial heterogeneity in a highly purified population of primitive HSC. Overall our
results indicate that mitochondrial heterogeneity might subdivide stem cell compartment into fractions with
distinct properties and activities. In addition, we have shown that the transcription factor FOXO3 that is
required for both normal hematopoietic and leukemic stem cell maintenance is essential for HSC
mitochondrial metabolism. Based on our studies and the similarities of normal blood-forming and leukemic
stem cells, we propose to test the hypothesis that deregulated FOXO3 activity promotes the generation of
pre-leukemic stem cells in the context of myeloid malignancies. We propose to test this hypothesis in a
model of MPN that designate a group of blood clonal stem cell disorders that have the potential to progress
to leukemia and in which metabolic/mitochondrial pathways have been broadly implicated. We will take
advantage of mitochondrial heterogeneity to identify subpopulations of HSC and LSC with distinct stem cell
properties and potential. Aim 1: To investigate functional consequences of Long-term-HSC
mitochondrial heterogeneity; Aim 2: To elucidate the mechanism of FOXO3 regulation of
mitochondria in stem cells. These studies are highly likely to improve our understanding of leukemic stem
cell biology and the contribution of mitochondria to the LSC generation.
摘要
常规和靶向治疗在根除骨髓恶性肿瘤方面几乎没有成功
包括骨髓增生性肿瘤(MPN)。无法可靠地防止产生小的
耐药干细胞样白血病细胞(或白血病干细胞(LSC))的子集,其引起复发,
无法瞄准LSC是造成这一失败的原因之一。线粒体代谢与
调节LSC和造血干细胞(HSC)活性,然而,
线粒体的功能,有助于健康的干细胞机制仍然在很大程度上未知。我们
在高度纯化的原始HSC群体中发现了线粒体异质性。总体上我们的
结果表明,线粒体异质性可能将干细胞区室细分为具有以下特征的组分:
不同的属性和活动。此外,我们已经证明,转录因子FOXO 3,
造血干细胞和白血病干细胞的正常维持所必需的是HSC
线粒体代谢根据我们的研究和正常造血和白血病的相似性,
干细胞,我们建议测试这一假设,即失调FOXO 3活性促进的产生,
白血病前干细胞在骨髓恶性肿瘤的情况下。我们建议在一个
MPN模型,指定一组具有进展潜力的血液克隆干细胞疾病
代谢/线粒体途径已被广泛牵连。我们将采取
线粒体异质性在鉴别具有不同干细胞的HSC和LSC亚群中的优势
性能和潜力。目的1:研究长期HSC的功能后果
目的2:阐明FOXO 3调节线粒体异质性的机制,
干细胞中的线粒体这些研究极有可能提高我们对白血病干细胞的认识
细胞生物学以及线粒体对LSC产生的贡献。
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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SAGHI GHAFFARI其他文献
SAGHI GHAFFARI的其他文献
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{{ truncateString('SAGHI GHAFFARI', 18)}}的其他基金
Towards Understanding Molecular Mechanisms of Human Hematopoietic Stem Cells' Quiescence
理解人类造血干细胞静止的分子机制
- 批准号:
10346063 - 财政年份:2022
- 资助金额:
$ 37.5万 - 项目类别:
Towards Understanding Molecular Mechanisms of Human Hematopoietic Stem Cells' Quiescence
理解人类造血干细胞静止的分子机制
- 批准号:
10570203 - 财政年份:2022
- 资助金额:
$ 37.5万 - 项目类别:
FOXO3 Regulation of Normal and Stress Erythropoiesis
FOXO3 对正常和应激性红细胞生成的调节
- 批准号:
9264330 - 财政年份:2017
- 资助金额:
$ 37.5万 - 项目类别:
Mitochondria in the Regulation of Terminal Erythropoiesis
线粒体对终末红细胞生成的调节
- 批准号:
10587056 - 财政年份:2017
- 资助金额:
$ 37.5万 - 项目类别:
FOXO3 Regulation of Normal and Stress Erythropoiesis
FOXO3 对正常和应激性红细胞生成的调节
- 批准号:
9403199 - 财政年份:2017
- 资助金额:
$ 37.5万 - 项目类别:
Lysosomes and their Communications with Mitochondria in Leukemic Stem Cell Disease Progression
白血病干细胞疾病进展中的溶酶体及其与线粒体的通讯
- 批准号:
10688239 - 财政年份:2016
- 资助金额:
$ 37.5万 - 项目类别:
(PQ5) Mitochondria in Leukemic Stem Cell Disease Progression
(PQ5) 白血病干细胞疾病进展中的线粒体
- 批准号:
9336279 - 财政年份:2016
- 资助金额:
$ 37.5万 - 项目类别:
(PQ5) Mitochondria in Leukemic Stem Cell Disease Progression
(PQ5) 白血病干细胞疾病进展中的线粒体
- 批准号:
9172951 - 财政年份:2016
- 资助金额:
$ 37.5万 - 项目类别:
Lysosomes and their Communications with Mitochondria in Leukemic Stem Cell Disease Progression
白血病干细胞疾病进展中的溶酶体及其与线粒体的通讯
- 批准号:
10522534 - 财政年份:2016
- 资助金额:
$ 37.5万 - 项目类别:
AKT Signaling and Oxidative Stress Regulation of Erythropoiesis
AKT 信号传导和红细胞生成的氧化应激调节
- 批准号:
8470631 - 财政年份:2009
- 资助金额:
$ 37.5万 - 项目类别:
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