Altered inflammatory response associated with acquired DNMT3A mutations
与获得性 DNMT3A 突变相关的炎症反应改变
基本信息
- 批准号:10394368
- 负责人:
- 金额:$ 74.88万
- 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:2021-05-01 至 2022-09-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgeAnimal ModelBindingBiological AssayBlood CellsCardiovascular DiseasesCell Differentiation processCell LineageCell modelCellsChromatinChromatin Remodeling FactorClonal ExpansionComputerized Medical RecordCoronary heart diseaseCoupledDNADNA MethylationDNMT3aDNMT3a mutationDataDefectDevelopmentDiagnosisDiseaseDisease modelElderlyEnrollmentEnzymesEpigenetic ProcessFunctional disorderGene ExpressionGene Expression RegulationGenesGeneticGenetic TranscriptionGenotypeGoalsHematologic NeoplasmsHematopoiesisHematopoieticHematopoietic stem cellsHumanIL6 geneImmunologyIndividualInflammationInflammatoryInflammatory ResponseInterleukin-6KnowledgeLinkMalignant NeoplasmsMediatingModelingMolecularMolecular ProfilingMusMutateMutationMutation AnalysisMyeloid CellsMyelopoiesisNucleic Acid Regulatory SequencesOrthologous GeneOutputPathologicPatientsPhenotypePopulation HeterogeneityPositioning AttributePredispositionPrevention approachProteinsProteomicsPublic HealthRegulator GenesRepressor ProteinsResearch PersonnelRiskRoleSourceStudy modelsSystemTechniquesTechnologyTimeUnited Statesagedaging populationbasebiobankcell typechromatin remodelingcohortcytokinedesigndrug use screeningepigenetic drugethnic diversitygenetic manipulationgenome editinggenome-widegenomic locushuman embryonic stem cellhuman pluripotent stem cellinduced pluripotent stem cellinsightmacrophagemonocytemutation carrierneutrophilnovelnovel strategiesnovel therapeutic interventionnull mutationpreventpromoterrecruitresponsesingle-cell RNA sequencingstem cell biologystem cell modeltranscription factortranscriptome sequencingtranscriptomics
项目摘要
PROJECT SUMMARY
The human gene DNMT3A encodes one of the three enzymes that carry out DNA methylation in
humans. Clonal expansion of blood cells with acquired mutations in DNMT3A is common in older adults,
occurring in 5-10 % of healthy individuals aged 60 or above. Carriers of DNMT3A mutations have an
approximately tenfold increased risk of developing hematologic cancers and are twice as likely to develop
coronary heart disease. Given the rapidly aging population in the United States and worldwide, understanding
the mechanistic basis of the association between acquired DNMT3A mutations in blood cells and increased
susceptibility to cancer and cardiovascular disease is tremendously important for public health. Recent studies
found evidence of increased inflammation mediated by myeloid cells when the ortholog of DNMT3A was
perturbed in animal models. However, the molecular mechanisms underlying this phenomenon and whether
DNMT3A mutations affect the inflammatory response of human myeloid cells remain poorly understood. To
address this gap in knowledge, we established an experimental system based on myeloid cells differentiated
from human pluripotent stem cells. Using this system, we found that human macrophages with DNMT3A
mutations displayed altered inflammatory response compared to wild-type macrophages, characterized by
augmented expression of IL-6, a potent proinflammatory cytokine. The IL6 promoter was one of the most
significantly hypomethylated loci in DNMT3A-mutated macrophages, suggesting a direct mechanistic link
between DNA methylation and inflammatory response in our model. In this application, we propose to
characterize the molecular signature of the inflammatory response associated with DNMT3A mutations using
genetically defined human macrophages and neutrophils and to dissect the epigenetic mechanisms underlying
DNMT3A-mediated gene expression regulation. In addition, we will examine the impact of harboring clonally
expanded blood cells with DNMT3A mutations on the inflammatory response of primary myeloid cells using a
novel single-cell transcriptomic technique. We are in an ideal position to pursue this project given the
availability of human pluripotent stem cell-based human myeloid cell models that we have developed and
validated, our access to a large biobank representing extremely diverse populations, and the assembly of a
strong scientific team consisting of investigators with complementary expertise. Findings from the proposed
study will provide critical new insights into the consequence of acquiring DNMT3A mutations on inflammation,
and help us develop novel strategies to prevent and treat pathologic conditions related to DNMT3A mutations.
项目总结
人类基因DNMT3A编码执行DNA甲基化的三种酶之一
人类。带有获得性DNMT3A突变的血细胞克隆性扩增在老年人中很常见,
在60岁或以上的健康人中,有5%-10%的人会发生这种情况。DNMT3A突变携带者有
患血液病的风险大约增加10倍,罹患血液病的可能性增加两倍
冠心病。鉴于美国和世界各地迅速老龄化的人口,理解
血细胞获得性DNMT3A突变与增高性疾病相关性的机制基础
对癌症和心血管疾病的易感性对公共健康极其重要。最新研究
当DNMT3A的同源基因被发现时,发现了髓系细胞介导的炎症增加的证据
对动物模型心烦意乱。然而,这种现象背后的分子机制以及是否
DNMT3A突变影响人类髓系细胞的炎症反应仍然知之甚少。至
针对这一认识空白,我们建立了基于髓系细胞分化的实验系统
来自人类多能干细胞。使用该系统,我们发现携带DNMT3A的人巨噬细胞
与野生型巨噬细胞相比,突变显示出炎症反应的改变,其特征是
IL-6的表达增强,这是一种强有力的促炎细胞因子。IL6的启动子是最多的
DNMT3A突变的巨噬细胞中显著低甲基化的基因座,提示有直接的机制联系
在我们的模型中,DNA甲基化和炎症反应之间的关系。在本申请中,我们建议
研究与DNMT3A突变相关的炎症反应的分子特征
从基因上定义人类巨噬细胞和中性粒细胞,并剖析潜在的表观遗传机制
DNMT3A介导的基因表达调控。此外,我们将研究克隆人窝藏的影响
扩增的DNMT3A突变血细胞对原代髓系细胞炎症反应的影响
新的单细胞转录切割技术。我们处于一个理想的位置来推进这个项目,因为
我们开发的基于人类多能干细胞的人髓系细胞模型的可用性
经过验证,我们可以访问代表极其不同人群的大型生物库,并组装一个
由具有互补专业知识的调查人员组成的强大的科学团队。建议的调查结果
这项研究将为获得DNMT3A突变对炎症的后果提供关键的新见解。
并帮助我们开发新的策略来预防和治疗与DNMT3A突变相关的病理情况。
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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{{ truncateString('Minji Byun', 18)}}的其他基金
Gene regulatory network modeling of disease-associated DNA methylation perturbations
疾病相关 DNA 甲基化扰动的基因调控网络建模
- 批准号:
10730859 - 财政年份:2023
- 资助金额:
$ 74.88万 - 项目类别:
Mechanistic modeling of epigenetic modifier mutations in human pluripotent stem cell-derived immune cells
人类多能干细胞衍生的免疫细胞表观遗传修饰突变的机制模型
- 批准号:
10733331 - 财政年份:2022
- 资助金额:
$ 74.88万 - 项目类别:
Mechanistic modeling of epigenetic modifier mutations in human pluripotent stem cell-derived immune cells
人类多能干细胞衍生的免疫细胞表观遗传修饰突变的机制模型
- 批准号:
10437235 - 财政年份:2022
- 资助金额:
$ 74.88万 - 项目类别:
Altered inflammatory response associated with acquired DNMT3A mutations
与获得性 DNMT3A 突变相关的炎症反应改变
- 批准号:
10746603 - 财政年份:2021
- 资助金额:
$ 74.88万 - 项目类别:
Altered inflammatory response associated with acquired DNMT3A mutations
与获得性 DNMT3A 突变相关的炎症反应改变
- 批准号:
10207988 - 财政年份:2021
- 资助金额:
$ 74.88万 - 项目类别:
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