The role of GSK3/PPAR-/mitophagy pathway in regulating hematopoia
GSK3/PPAR-/线粒体自噬通路在调节造血中的作用
基本信息
- 批准号:10545088
- 负责人:
- 金额:$ 51.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAgonistAllelesAttenuatedAutophagocytosisBiochemicalBiological AssayBlood CellsBone MarrowBone Marrow Stem Cell TransplantationBone Marrow TransplantationCell LineageClinicalDataDaughterDefectDiseaseDysmyelopoietic SyndromesExhibitsGenesGeneticGlycogen Synthase Kinase 3GoalsHematological DiseaseHematologyHematopoieticHematopoietic Stem Cell ResearchHematopoietic Stem Cell TransplantationHematopoietic stem cellsHomeostasisImpairmentKnock-outKnowledgeLearningLipidsMitochondriaMolecularMusOrganellesPPAR deltaPathway interactionsPeroxisome Proliferator-Activated ReceptorsPhenotypePhosphorylationPlayPopulationPreleukemiaPropertyProtein IsoformsPublishingRNA InterferenceRegulationReporterRoleSystemTestingTherapeuticTransgenic MiceTransplantationWorkexhaustionfatty acid oxidationgenetic approachhematopoietic differentiationhematopoietic stem cell expansionimprovedin vivoinhibitorinsightknock-downleukemialipid metabolismloss of functionnovelpharmacologicpreferencereconstitutionself-renewalstem cell divisionstem cell functionstem cell homeostasisstem cellsstemness
项目摘要
The role of GSK3/PPAR-δ/FAO/mitophagy pathway in regulating
hematopoietic stem cell homeostasis and function
Abstract
Hematopoietic stem cells (HSCs) possess the abilities to both produce stem cells, a
property known as self-renewal, and give rise to all differentiated hematopoietic lineages.
Clinically, HSCs are therapeutically valuable for transplantation in treatment of various
hematologic malignances. Despite remarkable progress made in the research of HSCs
during the past three decades, the molecular mechanisms regulating HSC homeostasis
and function are still not fully understood.
Our previous published showed that GSK3 plays an essential role in regulating HSC
homeostasis. Specifically, knockdown of Gsk3 promote transient expansion and long-term
exhaustion of HSC in vivo. Our new preliminary studies demonstrated that GSK3 functions
through PPAR-δ/FAO/mitophagy pathway to regulate HSC division symmetry; inhibition
of GSK3 induces mitophagy and conversely, blocking PPAR-δ/FAO/mitophagy can
reverse the enhanced self-renewal phenotype that is associated with GSK3 inhibition. In
this study, we will first examine how GSK3 regulates PPAR-δ, which in turn regulates
mitophagy and HSC division symmetry. Secondly, we will investigate whether loss-of-
function of Ppar-δ, Park2 or Pink1 (two mitophagy key regulators) reverse the functional
defect of Gsk3b-deficient HSC in vivo. Lastly, we will explore whether GSK3 controls FAO
and lipid metabolism to regulate HSC function and homeostasis.
Our study will provide significant new insights into the molecular mechanisms underlying
GSK3-dependent regulation of HSC homeostasis and function. The knowledge learned
may facilitate bone marrow transplantation for treating diverse hematological diseases.
GSK 3/PPAR-δ/FAO/线粒体自噬途径在调节细胞凋亡中的作用
造血干细胞稳态和功能
摘要
造血干细胞(HSC)具有产生干细胞,
这种特性称为自我更新,并产生所有分化的造血谱系。
在临床上,HSC对于移植治疗各种疾病是有治疗价值的。
血液恶性肿瘤尽管造血干细胞的研究取得了显著进展,
在过去的三十年中,调控HSC稳态的分子机制
和功能仍然没有完全理解。
我们以前的研究表明,GSK 3在调节HSC中起着重要作用,
体内平衡具体地,Gsk 3的敲低促进瞬时扩增和长期扩增。
体内HSC耗竭。我们新的初步研究表明,GSK 3的功能,
通过PPAR-δ/FAO/线粒体自噬途径调节HSC分裂对称性;抑制
GSK 3诱导线粒体自噬,相反,阻断PPAR-δ/FAO/线粒体自噬可
逆转与GSK 3抑制相关的增强的自我更新表型。在
在这项研究中,我们将首先研究GSK 3如何调节PPAR-δ,从而调节
线粒体自噬和HSC分裂对称性。其次,我们将调查是否失去-
Ppar-δ、Park 2或Pink 1(两种线粒体自噬关键调节因子)的功能逆转了
Gsk 3b缺陷型HSC的体内缺陷。最后,我们将探讨GSK 3是否控制粮农组织。
和脂质代谢来调节HSC功能和稳态。
我们的研究将提供重要的新见解的分子机制,
HSC稳态和功能的GSK 3依赖性调节。所学知识
可促进骨髓移植用于治疗多种血液病。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Jian Huang其他文献
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{{ truncateString('Jian Huang', 18)}}的其他基金
The role of GSK3/PPAR-/mitophagy pathway in regulating hematopoia
GSK3/PPAR-/线粒体自噬通路在调节造血中的作用
- 批准号:
10365005 - 财政年份:2022
- 资助金额:
$ 51.19万 - 项目类别:
Explore the signaling mechanisms of acquired resistance to tyrosine kinase inhibitors in AML
探索 AML 中酪氨酸激酶抑制剂获得性耐药的信号机制
- 批准号:
10363682 - 财政年份:2021
- 资助金额:
$ 51.19万 - 项目类别:
Explore the signaling mechanisms of acquired resistance to tyrosine kinase inhibitors in AML
探索 AML 酪氨酸激酶抑制剂获得性耐药的信号机制
- 批准号:
10589119 - 财政年份:2021
- 资助金额:
$ 51.19万 - 项目类别:
Small-molecule combinationsexpand hematopoietic stem cell ex vivo and in vivo
小分子组合在离体和体内扩增造血干细胞
- 批准号:
10018098 - 财政年份:2019
- 资助金额:
$ 51.19万 - 项目类别:
The Role of MicroRNA in Osteoarthritis: Alzheimer's Administrative Supplement
MicroRNA 在骨关节炎中的作用:阿尔茨海默病管理补充剂
- 批准号:
10287295 - 财政年份:2017
- 资助金额:
$ 51.19万 - 项目类别:
Signaling pathways regulated by GSK3 in hematopoietic stem cell
GSK3在造血干细胞中调控的信号通路
- 批准号:
8093631 - 财政年份:2011
- 资助金额:
$ 51.19万 - 项目类别:
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