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.
在美国,骨髓增生异常综合征(MDS)每年至少影响10,000人,在老年人群中尤为普遍。MDS是由造血干细胞(hsc)引起的一种克隆性疾病,其特征是髓系和红系分化受损以及基因组不稳定。目前很少有治疗方法可以改善MDS患者的细胞减少症。RNA剪接因子的突变
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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