THE ROLE OF SELENOPROTEIN SYNTHESIS PATHWAY IN ACUTE MYELOID LEUKEMIA
硒蛋白合成途径在急性髓系白血病中的作用
基本信息
- 批准号:10659193
- 负责人:
- 金额:$ 45.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAcute leukemiaAdultAffectAgeAmino AcidsAnabolismAnimal ModelAntioxidantsAttenuatedBindingBioinformaticsBiological AssayCRISPR screenCRISPR/Cas technologyCell DeathCell LineCellsClustered Regularly Interspaced Short Palindromic RepeatsCodon NucleotidesCoupledDataDatabasesDedicationsDependenceDietDiet therapyDietary SeleniumDropoutDrug Metabolic DetoxicationEnhancersFLT3 geneGene DeletionGenesHandHematopoiesisHomeostasisHumanKnockout MiceLipid PeroxidationLipid PeroxidesMLL-AF9MaintenanceMalignant NeoplasmsMetabolicMetabolismModelingMusMutationOrganismOxidation-ReductionOxidative StressPathway interactionsPatientsProductionPrognosisRegulationRoleSamplingSeleniumSelenocysteineTestingTherapeuticTrace ElementsTranslationsTransplantationXenograft procedureacute myeloid leukemia cellattenuationchemotherapycombinatorialconditional knockoutdietarydietary manipulationfeedinggenetic analysisgenetic approachglutathione peroxidaseimprovedin vivoinsightinterestleukemia treatmentleukemogenesismouse modelnovelnovel strategiesnovel therapeuticsolder patientpatient derived xenograft modelpolypeptideprotein expressionselenium deficiencyselenoproteintherapeutic targetthioredoxin reductasetranscription factorwhole genome
项目摘要
AML is the most common acute leukemia in adults, and it appears increasingly with age. Despite overall
improvement in the treatment of leukemia, AML still carries a devastating prognosis for elderly patients (less
than 10% of patients survive for 5 years). Thus, new therapies for AML are necessary. Using a bioinformatics
approach and a whole-genome CRISPR screening approach, we identified regulators of selenium metabolism
to be important for AML survival. Selenium is required for cells to synthesize selenocysteine, which is then used
to produce selenoproteins. Since many selenoproteins are involved in redox regulation, we hypothesized that
selenium metabolism is required for redox maintenance of AML. This hypothesis will be tested in the following
three aims. In aim 1, we will use mouse models that we have generated that have mutations in the genes we
identified in the CRISPR screen to examine the requirement of selenium metabolism in murine AML. In aim 2,
we will use a mouse model that lacks the redox regulator, which we hypothesize to be downstream of the
selenium metabolism pathway, to examine how this redox regulator promotes murine AML. In aim 3, we will
study the mechanisms we discovered in human AML patient-derived xenograft models to examine the
therapeutic potential of inhibiting selenium metabolism in AML. These genetic analyses with both murine and
human AML models should bring novel insights into how AML regulates selenium metabolism and the
therapeutic potential of targeting this mechanism.
急性髓系白血病是成人最常见的急性白血病,且随年龄增长而增多。尽管总体上
白血病治疗的进步,急性髓细胞白血病对老年患者的预后仍然是毁灭性的(更少
超过10%的患者存活5年)。因此,治疗AML的新疗法是必要的。使用生物信息学
方法和全基因组CRISPR筛选方法,我们确定了硒代谢的调节因子
对急性髓系白血病的生存至关重要。硒是细胞合成硒半胱氨酸所必需的,然后使用
来生产硒蛋白。由于许多硒蛋白参与氧化还原调节,我们假设
硒代谢是急性髓系白血病氧化还原维持所必需的。这一假设将在以下方面得到检验
三个目标。在目标1中,我们将使用我们产生的具有基因突变的小鼠模型
在CRISPR筛查中鉴定,以检查小鼠急性髓细胞白血病对硒代谢的需求。在目标2中,
我们将使用一个没有氧化还原调节器的小鼠模型,我们假设它在
硒代谢途径,以研究这种氧化还原调节因子如何促进小鼠急性髓系白血病。在《目标3》中,我们将
研究我们在人类AML患者来源的异种移植模型中发现的机制,以检查
抑制急性髓系白血病患者硒代谢的治疗潜力。这些对小鼠和小鼠的遗传分析
人类AML模型应该为AML如何调节硒代谢和
靶向这一机制的治疗潜力。
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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Daisuke Nakada其他文献
Daisuke Nakada的其他文献
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{{ truncateString('Daisuke Nakada', 18)}}的其他基金
Project 2: The role of the DNA damage response in clonal competition following genotoxic stress
项目 2:DNA 损伤反应在基因毒性应激后克隆竞争中的作用
- 批准号:
10332336 - 财政年份:2022
- 资助金额:
$ 45.55万 - 项目类别:
Mechanisms that regulate erythroid differentiation of hematopoietic stem cells
造血干细胞红系分化的调节机制
- 批准号:
10509652 - 财政年份:2022
- 资助金额:
$ 45.55万 - 项目类别:
Project 2: The role of the DNA damage response in clonal competition following genotoxic stress
项目 2:DNA 损伤反应在基因毒性应激后克隆竞争中的作用
- 批准号:
10606554 - 财政年份:2022
- 资助金额:
$ 45.55万 - 项目类别:
Mechanisms that regulate erythroid differentiation of hematopoietic stem cells
造血干细胞红系分化的调节机制
- 批准号:
10647781 - 财政年份:2022
- 资助金额:
$ 45.55万 - 项目类别:
THE ROLE OF SELENOPROTEIN SYNTHESIS PATHWAY IN ACUTE MYELOID LEUKEMIA
硒蛋白合成途径在急性髓系白血病中的作用
- 批准号:
10434125 - 财政年份:2021
- 资助金额:
$ 45.55万 - 项目类别:
THE ROLE OF SELENOPROTEIN SYNTHESIS PATHWAY IN ACUTE MYELOID LEUKEMIA
硒蛋白合成途径在急性髓系白血病中的作用
- 批准号:
10296885 - 财政年份:2021
- 资助金额:
$ 45.55万 - 项目类别:
Mesenchymal Stromal Cells Regulate Hematopoietic Stem Cell Aging
间充质基质细胞调节造血干细胞衰老
- 批准号:
9404451 - 财政年份:2016
- 资助金额:
$ 45.55万 - 项目类别:
Mesenchymal Stromal Cells Regulate Hematopoietic Stem Cell Aging
间充质基质细胞调节造血干细胞衰老
- 批准号:
9189715 - 财政年份:2016
- 资助金额:
$ 45.55万 - 项目类别:
Metabolic Regulation in Leukemia-Initatiating Cells
白血病起始细胞的代谢调节
- 批准号:
9245651 - 财政年份:2015
- 资助金额:
$ 45.55万 - 项目类别:
Metabolic Regulation in Leukemia-Initatiating Cells
白血病起始细胞的代谢调节
- 批准号:
9017971 - 财政年份:2015
- 资助金额:
$ 45.55万 - 项目类别:
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