Loss of progenitor function accelerates lung aging
Loss of progenitor function accelerates lung aging
批准号:
10579157
负责人:
SUSAN M MAJKA
金额:
$69.86万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-06-15 至 2028-02-29
关键词:
5 year oldAccelerationAddressAdultAgeAgingBiological AssayBiologyBlood VesselsCardiovascular systemCell CommunicationCell CountCell physiologyCellsCellular StructuresCharacteristicsChronicChronic Obstructive Pulmonary DiseaseChronic lung diseaseCoculture TechniquesCoupledDataDevelopmentDiseaseDistalEndotheliumFemaleFunctional disorderGoalsHistologicHomeostasisHumanImmuneImpairmentIn VitroInflammationInflammatoryInflammatory InfiltrateInterleukin-13KnowledgeLinkLungLung Lavage FluidLung diseasesLymphoidLymphoid CellMaintenanceMedialMesenchymalModelingMusOxidation-ReductionPatientsPhenotypePhysiologicalPhysiologyPlasmaPlayPopulationPredispositionProcessPrognosisProteinsPulmonary EmphysemaSamplingSenilitySmokerSmokingStromal CellsStructureStructure of parenchyma of lungSubgroupTestingTissuesVascular DiseasesVascular remodelingWorkagedaging populationangiogenesiscytokineepithelial stem cellexhaustionexposure to cigarette smokehuman modelimmune cell infiltratein vivoin vivo evaluationknock-downmalemouse modelnovelprematureprogenitorpulmonary functionstem cell functionstem cellstranscriptomics
中文摘要
衰老与肺结构丧失和功能下降有关。肺气肿性组织结构丧失
英文摘要
Aging is associated with loss of lung structure and declining function. Emphysematous loss of tissue structure
is exacerbated by vasculopathy, which increases susceptibility to lung disease, and limits survival. We have
previously demonstrated that the structure and function of the lung microvasculature is regulated by a
specialized mesenchymal vascular progenitor cell (MVPC). We have also defined Dickkopf-related protein
1 (DKK1) as a regulator of this niche in murine and human model. Our preliminary data demonstrate that
MVPC numbers decline with age in WT mice by 1 year, and that, when MVPC are depleted in young mice,
lung aging is accelerated, resulting in severe emphysema at 1.5 years of age. While MVPC are key modulators
of the pulmonary microvasculature in the distal lung, adventitial stem cells (ASC) influence large blood vessel
homeostasis in the proximal lung. Our preliminary data identifies key similarities between MVPCs and ASCs
suggesting that decline in ASC numbers and function may also result in accelerated lung aging. Given ASC
function is tightly controlled by lung-resident type-2 innate lymphoid cells (ILC2) and pulmonary ILC2 are
known to decrease with age, loss of ASC-ILC2 crosstalk is likely a contributor to emphysema. Similar to aging,
vascular remodeling is driven by chronic activation of type 2 (Th2) inflammation. Our preliminary data support
increased Th2 cytokine profiles in plasma and BAL of COPD patients. Human and murine scRNAseq data
define ILC2 and MVPC populations as well as immune cell infiltrate and cytokine expression characteristic of
Th2 inflammation in COPD and a smoking model. The goal of this proposal is to define the mechanisms that
result in loss of adult MVPC and ILC2 progenitor function contributing to accelerated lung aging, by altering
vascular structure and function, and increased susceptibility to emphysema in the aged population. We
hypothesize that loss of progenitor function accelerates lung aging by altering cell interactions within vascular
niches, promoting vascular remodeling and increasing susceptibility to emphysema in the aging population. We
will test that decline in MVPC and ILC2 numbers and/or function in the aging lung accelerates aging via
impairment of vascular homeostasis due to disruption of cell – cell interactions in their respective perivascular
niches, promoting vascular remodeling and loss of tissue structure using novel conditional murine models to
knock down progenitors in aged mice or young mice. We will assess the requirement of MVPC, MVPC derived
DKK1, ILC2 cells, and ILC2 derived IL13 in the maintenance of vascular niche homeostasis and susceptibility
to emphysema. We will use conditional models to manipulate DKK1 or IL13 expression in mice allowed to age
in the presence or absence of cigarette smoke exposure both in vivo and in vitro. Lastly, we will test that loss of
ILC2 and MVPC progenitors promotes lung aging and is associated with COPD and a type-2 immune
endotype. This work will provide an understanding of progenitor aging, mechanisms by which loss of MVPC
and ILC2 function drives vascular remodeling with a Th2 endotype contributing to lung aging and emphysema.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Mesenchymal Vascular Progenitor Depletion Promotes Lung Aging and Susceptibility to Emphysema
-
批准号:10353622
-
项目类别:
-
资助金额:$99.6万
-
财政年份:2022
-
负责人:SUSAN M MAJKA
-
依托单位:
Mesenchymal Vascular Progenitor Depletion Promotes Lung Aging and Susceptibility to Emphysema
-
批准号:10542770
-
项目类别:
-
资助金额:$99.6万
-
财政年份:2022
-
负责人:SUSAN M MAJKA
-
依托单位:
Loss of progenitor function accelerates lung aging
-
批准号:10426410
-
项目类别:
-
资助金额:$33.62万
-
财政年份:2021
-
负责人:SUSAN M MAJKA
-
依托单位:
Role of Lung MSC in Emphysema
-
批准号:10153854
-
项目类别:
-
资助金额:$61.68万
-
财政年份:2019
-
负责人:SUSAN M MAJKA
-
依托单位:
Role of Lung MSC in Emphysema
-
批准号:9705978
-
项目类别:
-
资助金额:$61.68万
-
财政年份:2019
-
负责人:SUSAN M MAJKA
-
依托单位:
Role of Lung MSC in Emphysema
-
批准号:9898030
-
项目类别:
-
资助金额:$63.29万
-
财政年份:2019
-
负责人:SUSAN M MAJKA
-
依托单位:
Role of Lung MSC in Emphysema
-
批准号:8848878
-
项目类别:
-
资助金额:$47.37万
-
财政年份:2013
-
负责人:SUSAN M MAJKA
-
依托单位:
Role of Lung MSC in Emphysema
-
批准号:8599945
-
项目类别:
-
资助金额:$51.87万
-
财政年份:2013
-
负责人:SUSAN M MAJKA
-
依托单位:
Role of Lung MSC in Emphysema
-
批准号:8704827
-
项目类别:
-
资助金额:$47.13万
-
财政年份:2013
-
负责人:SUSAN M MAJKA
-
依托单位:
Induced pluripotent stem cell therapy for lipodystrophy
-
批准号:8542832
-
项目类别:
-
资助金额:$18.82万
-
财政年份:2012
-
负责人:SUSAN M MAJKA
-
依托单位:
Induced pluripotent stem cell therapy for lipodystrophy
-
批准号:8372080
-
项目类别:
-
资助金额:$23.4万
-
财政年份:2012
-
负责人:SUSAN M MAJKA
-
依托单位:
Fate of Lung Stem Cells During Pulmonary Disease
-
批准号:8573490
-
项目类别:
-
资助金额:$36.75万
-
财政年份:2009
-
负责人:SUSAN M MAJKA
-
依托单位:
Fate of Lung Stem Cells During Pulmonary Disease
-
批准号:8308366
-
项目类别:
-
资助金额:$0.04万
-
财政年份:2009
-
负责人:SUSAN M MAJKA
-
依托单位:
Fate of Lung Stem Cells During Pulmonary Disease
-
批准号:7896563
-
项目类别:
-
资助金额:$37.16万
-
财政年份:2009
-
负责人:SUSAN M MAJKA
-
依托单位:
Fate of Lung Stem Cells During Pulmonary Disease
-
批准号:7728454
-
项目类别:
-
资助金额:$37.28万
-
财政年份:2009
-
负责人:SUSAN M MAJKA
-
依托单位:
Fate of Lung Stem Cells During Pulmonary Disease
-
批准号:8112658
-
项目类别:
-
资助金额:$37.16万
-
财政年份:2009
-
负责人:SUSAN M MAJKA
-
依托单位:
Skeletal Muscle Stem Cells Become Vascular Cells In Vivo
-
批准号:6404743
-
项目类别:
-
资助金额:$3.39万
-
财政年份:2001
-
负责人:SUSAN M MAJKA
-
依托单位:
海外基金