Mechanisms of marrow microenvironmental aging and their impact of progression of clonal hematopoiesis
骨髓微环境衰老机制及其对克隆造血进展的影响
基本信息
- 批准号:10665803
- 负责人:
- 金额:$ 53.49万
- 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:2022-07-15 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAcute Myelocytic LeukemiaAddressAgingAreaBiological MarkersBiology of AgingBone MarrowBone marrow failureCell AgingCell modelCellsChronicClinicalClonal ExpansionDNA RepairDNMT3aDataDevelopmentDysmyelopoietic SyndromesElderlyEpigenetic ProcessEventFailureFunctional disorderGene FrequencyGenesGenomeHIVHematopoiesisHematopoieticHematopoietic stem cellsHeterogeneityHomeostasisHumanIndividualInfectionInflammationInflammatoryInterleukin-1 betaInterventionKnowledgeLesionLongevityMacrophageMalignant NeoplasmsMarrowMissionModelingMolecularMorbidity - disease rateMusMutateMutationMyeloproliferative diseaseNatural ImmunityNucleotidesOrganismOxidoreductasePathologyPathway interactionsPatientsPersonsPharmaceutical PreparationsPhenotypePlayPopulationPreleukemiaProcessPublic HealthRNARecording of previous eventsRegulationReportingRepressionResearchResolutionRetrotranspositionRetrotransposonReverse Transcriptase InhibitorsReverse TranscriptionRiskRoleSirtuinsStromal CellsTestingTimeTranslationsTransplantationUnited States National Institutes of HealthWild Type MouseWorkage relatedagedbone agingcardiovascular risk factorclinical developmentdefined contributionderepressiondisabilityepigenomeexperimental studygenetic elementgenetic varianthematopoietic stem cell fatehigh riskimprovedinterestleukemialoss of functionmiddle agemortalitymutantnoveloverexpressionpreventprogression riskrisk predictionsenescencesex
项目摘要
Project Abstract
Mutated clones in hematopoietic cells, also known as clonal hematopoiesis (CH) are present in healthy
individuals and expand with aging. In spite of normal hematopoietic parameters, individuals with CH have
increased risk of myeloid neoplasms, cardiovascular risk and all-cause mortality. We recently showed that the
aged microenvironment contributes to hematopoietic stem cell fate choices. While the presence of clonal
hematopoiesis in healthy individuals has been widely reported, and its expansion with aging is established,
whether the aging microenvironment modifies clonal dynamics and contributes to clonal selection leading to
progression to myelodysplastic syndromes (MDS) remains unexplored. Sirtuin6/SIRT6 is a regulator of genome
and epigenome stability. SIRT6 is responsible for more efficient DNA repair in long-lived species. Moreover
SIRT6 plays a critical role in suppressing retrotransposon expression, demonstrating that retrotransposon activity
directly contributes to the progeroid phenotype in mice lacking SIRT6, in part through activation of innate
immunity. Nucleotide reverse transcriptase inhibitors (NRTIs) developed as HIV drugs, inhibit retrotransposition,
reduce inflammation, improve aging biomarkers in wild type mice, and extend the lifespan of progeroid mice
lacking SIRT6. We hypothesize that aging-associated de-repression of retrotransposons promotes pro-
inflammatory changes of specific hematopoietic stem cell-supportive niche populations (marrow macrophages
and multipotent stromal cells) which drive clonal progression to myeloid neoplasms. To test this hypothesis,
using relevant models of clonal hematopoiesis we will examine whether 1) pre-leukemic mutations form clones
and progress to MDS more readily in the aged microenvironment by transplanting them into young versus aged
recipient mice; 2) SIRT6 overexpression in key microenvironmental populations slows the rate of
microenvironmental and hematopoietic aging, clonal expansion and progression to MDS; 3) repressing LINE1
retrotranspositions with inhibitors of reverse transcriptases (NRTIs) slows clonal expansion and provides a
mechanism to discover novel microenvironmental regulators of clonal hematopoiesis progression.
项目摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Laura M Calvi其他文献
Laura M Calvi的其他文献
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{{ truncateString('Laura M Calvi', 18)}}的其他基金
Efferocytosis by Bone Marrow Stromal Cells and Bone Aging
骨髓基质细胞的胞吞作用和骨老化
- 批准号:
10629389 - 财政年份:2022
- 资助金额:
$ 53.49万 - 项目类别:
Efferocytosis by Bone Marrow Stromal Cells and Bone Aging
骨髓基质细胞的胞吞作用和骨老化
- 批准号:
10430637 - 财政年份:2022
- 资助金额:
$ 53.49万 - 项目类别:
PGE2 mitigation of acute and late radiation injury
PGE2 缓解急性和晚期放射损伤
- 批准号:
9540462 - 财政年份:2017
- 资助金额:
$ 53.49万 - 项目类别:
PGE2 mitigation of acute and late radiation injury
PGE2 缓解急性和晚期放射损伤
- 批准号:
8572275 - 财政年份:2013
- 资助金额:
$ 53.49万 - 项目类别:
PGE2 mitigation of acute and late radiation injury
PGE2 缓解急性和晚期辐射损伤
- 批准号:
8660638 - 财政年份:2013
- 资助金额:
$ 53.49万 - 项目类别:
PGE2 mitigation of acute and late radiation injury
PGE2 缓解急性和晚期辐射损伤
- 批准号:
8840882 - 财政年份:2013
- 资助金额:
$ 53.49万 - 项目类别:
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