Modifiable Drivers of Expansion and Malignant Transformation from Clonal Hematopoiesis
克隆造血扩张和恶性转化的可改变驱动因素
基本信息
- 批准号:10606550
- 负责人:
- 金额:$ 221.62万
- 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:2022-04-08 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAdultAgeApoptosisAtherosclerosis Risk in CommunitiesAttenuatedAutomobile DrivingBioinformaticsBlack raceBlood specimenBone MarrowCellsClinicalClonal ExpansionClone CellsCollaborationsCommunitiesCoupledDNA DamageDNA Sequence AlterationDNMT3aDataDevelopmentDiseaseElderlyEnsureEpigenetic ProcessEtiologyEvolutionExposure toFemaleGene MutationGenesGenotoxic StressGoalsHealthHematologic NeoplasmsHematopoiesisHematopoietic stem cellsHigh Fat DietHumanIncidenceIndividualInfectionInflammationInflammatoryInfrastructureInterventionLongevityMalignant - descriptorMalignant NeoplasmsMeasuresMetabolicMethylationModelingMultiomic DataMusMutationObesityOutcomeOxidative StressParticipantPathway interactionsPatientsPersonsPrecancerous ConditionsPrevention strategyProductionProteomicsPublicationsRecording of previous eventsRecordsRecurrenceResearch PersonnelRiskRisk FactorsRoleSamplingScientistSmokingSomatic MutationStressStudy modelsTestingTimeValidationVariantcancer preventionchemotherapycigarette smokingcohortepidemiological modelepidemiology studyexome sequencinggenotoxicitymetabolomicsmodifiable riskmortalitymosaicmouse modelmutantnon-geneticnovelperipheral bloodpremalignantprogramsresponserisk mitigationrisk stratificationsingle cell sequencingstressorsuccesstransplant model
项目摘要
Project Summary/Abstract
Clonal hematopoiesis (CH) is an age-associated pre-malignant condition in which the progeny of hematopoietic
stem and progenitor cells (HSPCs) with somatic mutations in about 20 genes dominate production of the
peripheral blood. While CH can persist without apparent health consequences for decades, it is associated with
increased risk for hematologic malignancies as well as all-cause mortality. Extrinsic conditions that favor
particular clones may separate asymptomatic CH carriers from those that progress to disease; yet, the specific
risk factors that can be modified to influence CH and its sequelae are largely unknown. The overall goal of this
Program, with three interactive Projects and two Cores, is to identify modifiable risk factors of CH-associated
HSPC expansion and subsequent malignant transformation, with a long-term view toward developing cancer
prevention strategies. A major feature of our Program is the use of novel mouse models to mimic CH and test
mechanisms that drive clone expansion and malignancy. In addition, our Program harnesses data from the
exceptional Atherosclerosis Risk in Communities (ARIC) study – which has followed more than 9,500 diverse
participants (27% Black, 55% female) over 30 years – to evaluate CH and malignancy risk in older adults. Project
1 models CH in mice, with an emphasis on HSPCs bearing mutations in epigenetic regulators (particularly
Dnmt3a and Tet2), to determine how inflammatory stress and metabolic changes promote expansion, including
cooperation between clones, and malignant transformation. Project 2 focuses on CH with DNA Damage
Response (DDR)-associated gene mutations, and how exposure to genotoxic stress from chemotherapy and
smoking enables clonal dominance and malignant transformation in mice. Both Projects 1 and 2 explore potential
interventions to suppress clone expansion. Project 3 analyzes the contribution of inflammation and DNA
damaging exposures to clonal expansion and malignant transformation in the ARIC cohort, capitalizing on
clinical, proteomic, methylation, whole exome sequencing, and metabolomic data already available. Project 3
will also perform single cell sequencing to determine changes in CH clonal contribution over time, including clonal
interactions, and the evolution to malignancy in the context of external stressors. The Projects are highly
interactive, with Projects 1 and 2 iteratively testing the causal and mechanistic influence of risk factors nominated
by preliminary studies and by Project 3, and Project 3 performing additional analyses to validate findings
generated by Projects 1 and 2. Projects 1 and 2 are mutually enhanced by shared approaches and data.
Together, all Projects will deconvolute the role of risk factors to CH and malignancy. The Program is supported
by a Single Cell Sequencing and Bioinformatics Core and an Administrative Core. By focusing on modifiable risk
factors, we can stratify the risk of hematologic malignancy to inform clinical guidance of individuals with CH. Our
expert team combines clinicians and scientists with long track records of successful collaboration. Together we
will address this critical problem for human health and longevity.
项目总结/文摘
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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MARGARET A. GOODELL其他文献
MARGARET A. GOODELL的其他文献
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{{ truncateString('MARGARET A. GOODELL', 18)}}的其他基金
Modifiable Drivers of Expansion and Malignant Transformation from Clonal Hematopoiesis
克隆造血扩张和恶性转化的可改变驱动因素
- 批准号:
10332334 - 财政年份:2022
- 资助金额:
$ 221.62万 - 项目类别:
A Mouse Model of DNMT3A-Associated Hematologic Malignancy
DNMT3A 相关血液恶性肿瘤的小鼠模型
- 批准号:
8926371 - 财政年份:2014
- 资助金额:
$ 221.62万 - 项目类别:
DNMT3A in Development of Hematologic Malignancies
DNMT3A 在血液恶性肿瘤发展中的作用
- 批准号:
10474446 - 财政年份:2014
- 资助金额:
$ 221.62万 - 项目类别:
A Mouse Model of DNMT3A-Associated Hematologic Malignancy
DNMT3A 相关血液恶性肿瘤的小鼠模型
- 批准号:
8761773 - 财政年份:2014
- 资助金额:
$ 221.62万 - 项目类别:
A Mouse Model of DNMT3A-Associated Hematologic Malignancy
DNMT3A 相关血液恶性肿瘤的小鼠模型
- 批准号:
9544059 - 财政年份:2014
- 资助金额:
$ 221.62万 - 项目类别:
DNMT3A in Development of Hematologic Malignancies
DNMT3A 在血液系统恶性肿瘤发展中的作用
- 批准号:
10689132 - 财政年份:2014
- 资助金额:
$ 221.62万 - 项目类别:
DNMT3A in Development of Hematologic Malignancies
DNMT3A 在血液恶性肿瘤发展中的作用
- 批准号:
10241920 - 财政年份:2014
- 资助金额:
$ 221.62万 - 项目类别:
A Mouse Model of DNMT3A-Associated Hematologic Malignancy
DNMT3A 相关血液恶性肿瘤的小鼠模型
- 批准号:
9318474 - 财政年份:2014
- 资助金额:
$ 221.62万 - 项目类别:
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