PI3 Kinase Inactivation in Myelodysplastic Syndrome
骨髓增生异常综合征中的 PI3 激酶失活
基本信息
- 批准号:10518821
- 负责人:
- 金额:$ 51.86万
- 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:2022-09-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAbnormal CellAffectAlternative SplicingAnimal ModelArginineAutophagocytosisBiological ModelsCellsClinicalCytokine SignalingDNA DamageDataData SetDefectDependenceDevelopmentDiseaseDysmyelopoietic SyndromesDysplasiaEventExonsGene ExpressionGene Expression ProfileGenesGenomic InstabilityGrowth FactorHematopoiesisHematopoieticHematopoietic Cell Growth FactorsHematopoietic stem cellsHemorrhageHumanImpairmentInfectionKnock-outKnockout MiceLeadLinkLipidsMaintenanceMessenger RNAMetforminModelingMusMutationMyelogenousNuclearPTEN genePathogenesisPathway interactionsPatientsPatternPersonsPharmacologyPhenotypePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPhysiologicalPlayProcessProtein IsoformsProtein KinaseProteinsProto-Oncogene Proteins c-aktQuality ControlRNA SplicingRNA-Binding ProteinsRecyclingReportingRoleSRSF2 geneSamplingSerineSignal TransductionSpliceosomesTestingTherapeuticTransfusionaging populationbiological adaptation to stresscytopeniadrug candidateerythroid differentiationexon skippinghematopoietic stem cell differentiationimprovedinhibitormortalitymouse modelmutantnovel therapeutic interventionpreventpublic health relevancestem cell biologystem cell functionstem cell genesstem cellstherapeutic target
项目摘要
Myelodysplastic Syndrome (MDS) affects at least 10,000 people each year in the U.S., and is particularly prevalent in the aging population. MDS is a clonal disorder arising in hematopoietic stem cells (HSCs), characterized by impaired myeloid and erythroid differentiation and genomic instability. There are currently few therapeutic approaches available to improve cytopenias in MDS patients. Mutations in RNA splicing factors are
observed in 50% of MDS cases, and are important contributors to MDS initiation and progression. Most hematopoietic growth factors and cytokines signal through the PI3 kinase (PI3K)/AKT pathway. We have found that compound deletion of the three PI3K isoforms P110a, b, and d in mouse hematopoietic cells leads to a phenotype resembling MDS, with cytopenias, impaired HSC differentiation and genomic instability. Interestingly, we observed enrichment of our TKO HSC expression signature in an MDS patient gene expression dataset. Furthermore, a subset of MDS samples have elevated expression levels of the negative regulator PTEN, suggesting functional inactivation of PI3K in these MDS patients. Our preliminary data reveals that HSCs in PI3K triple knockout (TKO) mice have a defect in autophagy, an intracellular recycling mechanism that is important for the maintenance of HSC differentiation. We found that pharmacologic induction of autophagy can improve differentiation of TKO HSCs. We also observed widespread alterations in mRNA splicing in TKO HSCs. Therefore, PI3K TKO mice are a valuable new model system to study the mechanisms of MDS initiation and progression. We hypothesize that maintenance of PI3K signaling in HSCs is
required to maintain HSC differentiation and to protect HSCs from DNA damage. We propose to (1) determine whether induction of autophagy can improve myeloid and erythroid differentiation in MDS patient samples, (2) delineate the mechanism by which PI3K and its downstream kinase AKT control mRNA splicing in HSCs and in MDS, and (3) determine whether MDS cells with splicing factor mutations are more sensitive to inhibition of PI3K/AKT signaling. These approaches will further our understanding of how growth factor and cytokine signaling regulates autophagy and mRNA splicing through PI3K/AKT in MDS initiation. We also plan to test several therapeutic approaches to improve differentiation in MDS, including induction of autophagy and inhibition of PI3K/AKT in MDS with splicing factor mutations.
骨髓增生异常综合征(MDS)在美国每年影响至少10,000人,并且在老龄人口中特别普遍。MDS是造血干细胞(HSC)中出现的克隆性疾病,其特征在于髓系和红系分化受损和基因组不稳定。目前几乎没有治疗方法可用于改善MDS患者的血细胞减少症。RNA剪接因子的突变是
在50%的MDS病例中观察到,并且是MDS开始和进展的重要贡献者。大多数造血生长因子和细胞因子通过PI 3激酶(PI 3 K)/AKT途径进行信号传导。我们已经发现,在小鼠造血细胞中三种PI 3 K亚型P110 a、B和d的复合缺失导致类似MDS的表型,具有血细胞减少、受损的HSC分化和基因组不稳定性。有趣的是,我们在MDS患者基因表达数据集中观察到我们的TKO HSC表达特征的富集。此外,MDS样品的子集具有升高的负调节因子PTEN表达水平,表明这些MDS患者中PI 3 K的功能失活。我们的初步数据显示,PI 3 K三重敲除(TKO)小鼠中的HSC在自噬方面存在缺陷,自噬是一种对维持HSC分化至关重要的细胞内再循环机制。我们发现药物诱导自噬可以提高TKO HSC的分化。我们还观察到TKO HSC中mRNA剪接的广泛改变。因此,PI 3 K TKO小鼠是研究MDS发生和发展机制的一个有价值的新模型系统。我们假设HSC中PI 3 K信号的维持是
这是维持HSC分化和保护HSC免受DNA损伤所必需的。我们建议(1)确定诱导自噬是否可以改善MDS患者样本中的髓系和红系分化,(2)描述PI 3 K及其下游激酶AKT控制HSC和MDS中mRNA剪接的机制,以及(3)确定具有剪接因子突变的MDS细胞是否对PI 3 K/AKT信号传导的抑制更敏感。这些方法将进一步我们的理解,如何生长因子和细胞因子信号调节自噬和mRNA剪接通过PI 3 K/AKT在MDS的启动。我们还计划测试几种改善MDS分化的治疗方法,包括诱导自噬和抑制剪接因子突变的MDS中的PI 3 K/AKT。
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)
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Kira Gritsman其他文献
Kira Gritsman的其他文献
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{{ truncateString('Kira Gritsman', 18)}}的其他基金
PI3 Kinase Inactivation in Myelodysplastic Syndrome
骨髓增生异常综合征中的 PI3 激酶失活
- 批准号:
10669279 - 财政年份:2022
- 资助金额:
$ 51.86万 - 项目类别:
PI3 Kinase Inactivation in Myelodysplastic Syndrome
骨髓增生异常综合征中的 PI3 激酶失活
- 批准号:
10476196 - 财政年份:2021
- 资助金额:
$ 51.86万 - 项目类别:
PI3K Isoform Dependence in Adult Hematopoiesis and Myeloid Leukemia
成人造血和髓性白血病中 PI3K 同工型依赖性
- 批准号:
9103377 - 财政年份:2016
- 资助金额:
$ 51.86万 - 项目类别:
PI3K Isoform Dependence in Adult Hematopoiesis and Myeloid Leukemia
成人造血和髓性白血病中 PI3K 同工型依赖性
- 批准号:
9251260 - 财政年份:2016
- 资助金额:
$ 51.86万 - 项目类别:
The p110 alpha and delta isoforms of PI3 kinase in hematopoiesis and leukemia
造血和白血病中 PI3 激酶的 p110 α 和 δ 亚型
- 批准号:
8139891 - 财政年份:2010
- 资助金额:
$ 51.86万 - 项目类别:
The p110 alpha and delta isoforms of PI3 kinase in hematopoiesis and leukemia
造血和白血病中 PI3 激酶的 p110 α 和 δ 亚型
- 批准号:
8315741 - 财政年份:2010
- 资助金额:
$ 51.86万 - 项目类别:
The p110 alpha and delta isoforms of PI3 kinase in hematopoiesis and leukemia
造血和白血病中 PI3 激酶的 p110 α 和 δ 亚型
- 批准号:
8886573 - 财政年份:2010
- 资助金额:
$ 51.86万 - 项目类别:
The p110 alpha and delta isoforms of PI3 kinase in hematopoiesis and leukemia
造血和白血病中 PI3 激酶的 p110 α 和 δ 亚型
- 批准号:
8530989 - 财政年份:2010
- 资助金额:
$ 51.86万 - 项目类别:
The p110 alpha and delta isoforms of PI3 kinase in hematopoiesis and leukemia
造血和白血病中 PI3 激酶的 p110 α 和 δ 亚型
- 批准号:
7867650 - 财政年份:2010
- 资助金额:
$ 51.86万 - 项目类别:
Regulation and function of hematopoietic stem cell niches
造血干细胞生态位的调节和功能
- 批准号:
10507236 - 财政年份:2000
- 资助金额:
$ 51.86万 - 项目类别:
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