MYCT1 as a moderator for signaling between human HSC and their niche
MYCT1 作为人类 HSC 与其生态位之间信号传导的调节剂
基本信息
- 批准号:10593103
- 负责人:
- 金额:$ 31.2万
- 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:2022-04-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectBiological AssayBloodBlood CellsCell Cycle ProgressionCell LineCell divisionCell physiologyCellsClinicalCuesDataEndocytosisEndosomesEndothelial CellsEngraftmentEnvironmentEquilibriumFunctional disorderGene ExpressionGenesHematologic NeoplasmsHematological DiseaseHematopoiesisHematopoietic Cell ProductionHematopoietic Stem Cell TransplantationHematopoietic stem cellsHumanInheritedKineticsLifeLinkMLLT3 geneMediatingModelingMolecularMusNatural regenerationPatientsProteinsReceptor SignalingRegulationSignal PathwaySignal TransductionTGFBR1 geneTGFBR2 geneTherapeuticTransforming Growth Factor betaTransplantationVesicleWorkclinical applicationethnic biasethnic minorityexpression vectorextracellularfunctional improvementgain of functionhematopoietic stem cell expansionhematopoietic stem cell nicheimprovedinsightknock-downloss of functionmutantnovelnovel strategiesoverexpressionpreventprocess improvementprogramsresponseself-renewalstem cell divisionstem cell functionstem-like cellstemnesstransplantation therapy
项目摘要
SUMMARY
Hematopoietic stem cells (HSC) need to integrate microenvironmental cues to switch their fate between
quiescence, self-renewal, and differentiation, thereby sustaining hematopoiesis through life. However, the
molecular programs governing HSC stemness become grossly dysregulated during culture, hindering our ability
to expand functional HSCs for treating hematological diseases. Our data uncovered MYCT1 (Myc target 1) as
human HSC regulatory factor that is critical for their expansion and engraftment, but becomes suppressed during
differentiation and culture. We found that MYCT1 localizes in endosomes, interacts with vesicle components and
signaling receptors with critical functions in HSCs (e.g. TGFBR1 and 2), and controls the rate of endocytosis,
which modulates cell signaling and must be tightly regulated to maintain HSC stemness. Many genes
dysregulated upon MYCT1 knockdown (KD) are linked to HSC division and self-renewal. We hypothesize that
MYCT1 governs HSC stemness and their ability to balance between fate options by fine-tuning multiple signaling
cues through the control of endocytosis. We have created a toolbox of MYCT1 knockdown and overexpression
vectors, including various MYCT1 deletion mutants, that can be used in primary human HSPCs as well as HSC-
like and endothelial cell line models to investigate MYCT1 mechanism of action. We will investigate how MYCT1-
mediated control of endocytosis affects signaling in HSCs, and how this influences HSC cell-fate decisions
including quiescence and asymmetric vs symmetric division. We will then assess if rescuing MYCT1 regulated
processes improves the function of cultured human HSC, including those expanded using MLLT3
overexpression. Our work may open up new strategies to maintain HSC transplantability during ex vivo
expansion and ultimately help broaden HSC clinical applications.
概括
造血干细胞(HSC)需要整合微环境线索来改变它们的命运
静止、自我更新和分化,从而维持整个生命的造血作用。然而,
控制 HSC 干性的分子程序在培养过程中变得严重失调,阻碍了我们的能力
扩大用于治疗血液疾病的功能性造血干细胞。我们的数据发现 MYCT1(Myc 目标 1)为
人类 HSC 调节因子,对其扩张和植入至关重要,但在复制过程中受到抑制
差异化和文化。我们发现 MYCT1 定位于内体中,与囊泡成分相互作用并
在 HSC 中具有关键功能的信号传导受体(例如 TGFBR1 和 2),并控制内吞速率,
它调节细胞信号传导,必须严格调节以维持 HSC 干性。许多基因
MYCT1 敲低 (KD) 后的失调与 HSC 分裂和自我更新有关。我们假设
MYCT1 通过微调多个信号来控制 HSC 干性及其在命运选择之间平衡的能力
通过内吞作用的控制来提示。我们创建了 MYCT1 敲低和过表达工具箱
载体,包括各种 MYCT1 缺失突变体,可用于原代人类 HSPC 以及 HSC-
样和内皮细胞系模型来研究 MYCT1 的作用机制。我们将研究 MYCT1-
内吞作用介导的控制影响 HSC 中的信号传导,以及这如何影响 HSC 细胞的命运决定
包括静止和不对称与对称分裂。然后我们将评估拯救 MYCT1 是否受到监管
过程改善了培养的人类 HSC 的功能,包括使用 MLLT3 扩展的那些
过度表达。我们的工作可能会开辟新的策略来维持体外造血干细胞的可移植性
扩展并最终帮助扩大 HSC 临床应用。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Hanna Katri Annikki Mikkola其他文献
Hanna Katri Annikki Mikkola的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Hanna Katri Annikki Mikkola', 18)}}的其他基金
MYCT1 as a moderator for signaling between human HSC and their niche
MYCT1 作为人类 HSC 与其生态位之间信号传导的调节剂
- 批准号:
10392239 - 财政年份:2022
- 资助金额:
$ 31.2万 - 项目类别:
Mapping human hematopoietic stem cell development
绘制人类造血干细胞发育图谱
- 批准号:
10435434 - 财政年份:2021
- 资助金额:
$ 31.2万 - 项目类别:
Mapping human hematopoietic stem cell development
绘制人类造血干细胞发育图谱
- 批准号:
10633115 - 财政年份:2021
- 资助金额:
$ 31.2万 - 项目类别:
Mapping human hematopoietic stem cell development
绘制人类造血干细胞发育图谱
- 批准号:
9998658 - 财政年份:2021
- 资助金额:
$ 31.2万 - 项目类别:
Defining the mechanisms regulating MLLT3 expression in human hematopoietic stem cells
定义人类造血干细胞中 MLLT3 表达的调节机制
- 批准号:
10113603 - 财政年份:2019
- 资助金额:
$ 31.2万 - 项目类别:
Defining the mechanisms regulating MLLT3 expression in human hematopoietic stem cells
定义人类造血干细胞中 MLLT3 表达的调节机制
- 批准号:
9766113 - 财政年份:2019
- 资助金额:
$ 31.2万 - 项目类别:
Defining the mechanisms regulating MLLT3 expression in human hematopoietic stem cells
定义人类造血干细胞中 MLLT3 表达的调节机制
- 批准号:
9894797 - 财政年份:2019
- 资助金额:
$ 31.2万 - 项目类别:
Defining the self-renewal program in human hematopoietic stem cells
定义人类造血干细胞的自我更新程序
- 批准号:
8934081 - 财政年份:2014
- 资助金额:
$ 31.2万 - 项目类别:
Defining the Self-Renewal Program in Human Hematopoietic Stem Cells
定义人类造血干细胞的自我更新程序
- 批准号:
10210386 - 财政年份:2014
- 资助金额:
$ 31.2万 - 项目类别:
Defining the Self-Renewal Program in Human Hematopoietic Stem Cells
定义人类造血干细胞的自我更新程序
- 批准号:
10443733 - 财政年份:2014
- 资助金额:
$ 31.2万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 31.2万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 31.2万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 31.2万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 31.2万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 31.2万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 31.2万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 31.2万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 31.2万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 31.2万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 31.2万 - 项目类别:
Grant-in-Aid for Early-Career Scientists














{{item.name}}会员




