Accelerated Aging as a Cause of Chronic Lung Allograft Dysfunction
加速衰老是慢性同种异体肺移植功能障碍的原因
基本信息
- 批准号:10409672
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Acute Lung InjuryAffectAgeAgingAllograftingAwardBiological MarkersBiopsyBiopsy SpecimenBronchiolitisCell AgingCellsCessation of lifeCharacteristicsChromosomesChronicClinicalCohort StudiesCox ModelsCox Proportional Hazards ModelsDNA MethylationDNA RepairDataDevelopmentDiagnosticDiseaseDonor SelectionDonor personEnrollmentEpigenetic ProcessEpithelialEpithelial CellsFailureFibrosisFluorescent in Situ HybridizationFunctional disorderGenesGenetic PolymorphismGenetic RiskGenetic VariationGenotypeHandHumanImmuneImmune responseImmunofluorescence ImmunologicImmunosuppressionImpairmentIn VitroInflammationInjuryInterventionInvestigationLeadLengthLightLinear ModelsLinkLongitudinal cohortLungLung TransplantationLung diseasesLymphocyteMeasurementMeasuresMediatingMethylationMolecularMusNeurodegenerative DisordersNucleoproteinsOrganOutcomePathogenesisPathologicPathway interactionsPerioperativePeripheralPeripheral Blood Mononuclear CellPhenotypePlasmaPlasma CellsPlayPrevalenceProliferatingPulmonary InflammationRNARapid diagnosticsRehabilitation therapyRisk AssessmentRisk FactorsRoleSamplingSolidTelomere ShorteningTestingTherapeutic InterventionTimeTissuesTransplant RecipientsTransplantationVeteransairway epitheliumairway regenerationbasebisulfite sequencingcell free DNAcell injurycell typecohortconstrictiondigitalepithelial stem cellfibrotic lung diseasegenetic variantgraft dysfunctionidiopathic pulmonary fibrosisimproved outcomeinjured airwayinnovationinsightlung allograftmethylation patternmortality riskmouse modelnext generationnovelnovel markerperipheral bloodpost-transplantprospectiverecruitresponsestem cellstechnology developmenttelomeretranscriptomics
项目摘要
Lung transplantation is a lifesaving option for veterans with end-stage lung diseases, in particular idiopathic
pulmonary fibrosis (IPF). Veterans appear to be disproportionately affected by IPF, a disease that has been
described as early aging of the lung. IPF is usually fatal unless the lungs are replaced by transplant. Even
following lung transplantation median survival is less than six years, limited primarily by chronic lung allograft
dysfunction (CLAD). Emerging data suggest that telomeres, the nucleoprotein caps that protect chromosomes
during cellular replication, are involved in IPF, but it is unknown whether telomeres also play a role in CLAD.
Were that to be the case, the same pathophysiology that necessitated transplant might also underlie its failure.
Our own preliminary data show that impaired telomeres in peripheral blood of lung allograft donors are linked
to decreased survival in lung allograft recipients. We also have found that telomere dysfunction in airway stem
cells is sufficient to induce the pathologic hallmarks of CLAD in an experimental murine model. In humans,
airway progenitor cells proliferate and differentiate to restore airway epithelial integrity following injury. Thus,
telomere dysfunction could lead to airway epithelial cell progenitor failure, resulting in denuded airways that
are subsequently replaced by fibrotic tissue. With the support of this Merit Award, we will test the innovative
hypothesis that telomere dysfunction leads to CLAD. In Study Aim 1, we will evaluate the associations
between telomere genetic variants and CLAD in a large established multi-center cohort of lung transplant
recipients. Common genetic variants resulting in short telomeres will be sequenced from donor cells, and
telomere length will be determined by quantitative PCR. We will use adjusted Cox proportional hazards
models to evaluate the links between donor telomere length or genotype and post-transplant survival time.
Novel genotypic associations with telomere dysfunction will be validated in vitro. These findings will help
distinguish the contributions of innate and acquired telomere dysfunction to poor post-transplant outcomes.
Study Aim 2 will test the association between short allograft epithelial cell telomeres and CLAD-free survival
in a longitudinal cohort. Epithelial telomere lengths will be determined by fluorescence-in situ hybridization
with a telomere-specific probe (Telo-FISH) on endobronchial and transbronchial biopsy tissues. We will test
the association between telomere length and CLAD-free survival using adjusted Cox models and examine
transcriptomic sequelae of telomere dysfunction. In Study Aim 3, we will determine whether airway epithelial
cell injury is associated with allograft telomere shortening and epigenetic aging in a prospectively enrolled
cohort of lung transplant recipients. Early allograft injury will be assessed clinically by the presence of primary
graft dysfunction (PGD). We also quantify allograft epithelial cell injury from recipient plasma cell-free DNA
using next-generation bisulfite sequencing to enumerate donor-specific polymorphisms and cell-type specific
DNA methylation patterns. We will test for associations between PGD and cell-free DNA measurements of
allograft injury with telomere-based and epigenetic metrics of allograft aging using adjusted linear models.
These findings will shed light on the longstanding question of how acute lung injury and inflammation develop
into chronic fibrosis. Further, these studies could establish that CLAD is an evoked phenotype in which
telomere dysfunction leads to impaired epithelial responses to chronic transplant-associated airway injury.
Overall, this proposed investigation has the potential to reshape our conceptual understanding of CLAD and
lead to novel biomarkers that could inform cutting edge therapeutic interventions. This would be new
paradigm, potentially transforming our approach CLAD and thus improving outcomes for veterans with end-
stage lung disease.
肺移植是一个挽救生命的选择,退伍军人终末期肺病,特别是特发性
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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JOHN GREENLAND其他文献
JOHN GREENLAND的其他文献
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{{ truncateString('JOHN GREENLAND', 18)}}的其他基金
Telomere Dysfunction as a cause of Chronic Lung Allograft Dysfunction
端粒功能障碍是慢性同种异体肺移植功能障碍的原因
- 批准号:
10772852 - 财政年份:2023
- 资助金额:
-- - 项目类别:
The Clinical and Molecular Impacts of Lung Primary Graft Dysfunction
原发性移植肺功能障碍的临床和分子影响
- 批准号:
10677642 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Airway epithelial cell and lymphocyte interactions in chronic lung allograft dysfunction pathogenesis
慢性肺同种异体移植功能障碍发病机制中气道上皮细胞和淋巴细胞的相互作用
- 批准号:
10684231 - 财政年份:2022
- 资助金额:
-- - 项目类别:
The Clinical and Molecular Impacts of Lung Primary Graft Dysfunction
原发性移植肺功能障碍的临床和分子影响
- 批准号:
10430393 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Airway epithelial cell and lymphocyte interactions in chronic lung allograft dysfunction pathogenesis
慢性肺同种异体移植功能障碍发病机制中气道上皮细胞和淋巴细胞的相互作用
- 批准号:
10521842 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Telomere Dysfunction as a cause of Chronic Lung Allograft Dysfunction
端粒功能障碍是慢性同种异体肺移植功能障碍的原因
- 批准号:
10609432 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Telomere Dysfunction as a cause of Chronic Lung Allograft Dysfunction
端粒功能障碍是慢性同种异体肺移植功能障碍的原因
- 批准号:
10397632 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Telomere Dysfunction as a cause of Chronic Lung Allograft Dysfunction
端粒功能障碍是慢性同种异体肺移植功能障碍的原因
- 批准号:
10161858 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Accelerated Aging as a Cause of Chronic Lung Allograft Dysfunction
加速衰老是慢性同种异体肺移植功能障碍的原因
- 批准号:
10196968 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Accelerated Aging as a Cause of Chronic Lung Allograft Dysfunction
加速衰老是慢性同种异体肺移植功能障碍的原因
- 批准号:
10662220 - 财政年份:2020
- 资助金额:
-- - 项目类别:
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