Aging and dysfunction of progenitor niches: Role of Del-1
祖细胞生态位的衰老和功能障碍:Del-1 的作用
基本信息
- 批准号:10536596
- 负责人:
- 金额:$ 33.42万
- 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:2020-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgeAge MonthsAgingAnimal ModelApoptoticAreaBackBiological AssayBiologyBone RegenerationBone TissueCellsChronicCollaborationsDefectDevelopmentDiseaseElderlyEndothelial CellsEndotheliumFunctional disorderGeneticGermanyHomeostasisHumanITGB3 geneImmune responseImmunityImpairmentIn VitroInflammationInflammatoryIntegrinsIntervention StudiesInvestmentsKnock-outLeukocytesLocationMAPK3 geneMacrophageMesenchymalMesenchymal Stem CellsModelingMolecularMusNeutrophil InfiltrationOsteogenesisPTK2 genePaperPennsylvaniaPeriodontal DiseasesPeriodontal LigamentPeriodontitisPeriodontiumPredispositionPrevalenceProcessProliferatingProtein SecretionProteinsPsychiatryPublicationsRGD (sequence)Regenerative capacityRejuvenationResearchResolutionRoleSeveritiesSignal TransductionSourceTestingTherapeuticTissuesTooth structureTransgenic OrganismsUniversitiesWorkage relatedagedalveolar bonebone lossexperimental studyhuman old age (65+)immunoregulationimprovedin vivoin vivo Modelinsightmutantneutrophilnovelosteoblast differentiationosteogenicosteoprogenitor celloverexpressionprogenitorreceptorrecruitregeneration potentialregenerativerepairedstem cell nichestem cell self renewalstem cellstissue regenerationtissue repairtooltranscription factor
项目摘要
Project Summary
The elderly have increased susceptibility to periodontitis, a prevalent inflammatory disease that causes
destruction of the tooth-supporting tissues (periodontium). This increased susceptibility is likely caused by
alterations to the immuno-inflammatory status and/or regenerative potential of the periodontal tissue. Impaired
tissue regeneration may be traced back to age-related alterations in the mesenchymal stem cell (MSC) niche of
the periodontal ligament (PDL), harboring the osteoprogenitors. Del-1 is a homeostatic protein secreted by
distinct tissue resident cells: It regulates the recruitment of neutrophils (endothelial cell-derived Del-1) and the
efferocytosis of apoptotic neutrophils (macrophage-derived Del-1), thus Del-1 controls both the initiation and
resolution of inflammation. Additional research has shown that Del-1 is produced in the PDL and promotes
osteoblastic differentiation as well as induces the formation of new alveolar bone during resolution of
experimental periodontitis. However, Del-1 expression is severely diminished in old age. This project investigates
the overarching hypothesis that the aging-related Del-1 deficiency may contribute to the dysregulation of
osteogenesis, thereby leading to defective periodontal bone regeneration in old age. This proposal comprises
two specific aims and focuses on relevant animal model-based mechanistic and intervention studies, including
mice with lineage-specific deletions or overexpression of Del-1 or its receptor β3 integrin. In Aim 1, it is proposed
that Del-1 promotes osteoblastic differentiation by acting via its RGD motif on β3 integrin in osteolineage
progenitors. Aim 2 involves the elucidation of the mechanisms by which Del-1 regulates osteogenesis in vivo
and, moreover, examines the consequences of aging-related Del-1 deficiency on bone regeneration. It is also
proposed that impaired bone regeneration in old mice can be reversed by local administration of Del-1. On the
basis that the regenerative defect of the aged PDL-MSC niche is reversible and regulated by the extrinsic
microenvironment, the findings of this proposal may potentially pave the way to novel Del-1-based approaches
to rejuvenate niche functionality and thus enhance periodontal bone regeneration in old age.
项目摘要
老年人对牙周炎的易感性增加,牙周炎是一种常见的炎症性疾病,可导致
破坏牙齿支持组织(牙周组织)。这种易感性的增加很可能是由
牙周组织免疫炎症状态和/或再生潜能的改变。受损的
组织再生可以追溯到与年龄相关的骨髓间充质干细胞(MSC)利基的改变
牙周膜(PDL),含有骨祖细胞。Del-1是一种体内平衡蛋白,由
独特的组织驻留细胞:它调节中性粒细胞(内皮细胞衍生的Del-1)的募集和
吞噬凋亡的中性粒细胞(巨噬细胞衍生的Del-1),因此Del-1同时控制启动和
消退炎症。其他研究表明,Del-1在PDL中产生,并促进
成骨细胞分化和诱导新牙槽骨的形成
实验性牙周炎。然而,Del-1的表达在老年时会严重减弱。这个项目调查了
最重要的假设是,与衰老相关的Del-1缺乏可能导致了
成骨,从而导致老年牙周骨再生缺陷。这项建议包括
两个具体目标,并侧重于相关的基于动物模型的机制和干预研究,包括
具有Del-1或其受体β3整合素的谱系特异性缺失或过度表达的小鼠。在目标1中,建议
Del-1通过其RGD域作用于β3整合素促进成骨细胞分化
祖先。目的2阐明Del-1在体内调节成骨的机制
此外,还研究了与衰老相关的Del-1缺乏对骨骼再生的影响。它也是
提出局部应用Del-1可以逆转老年小鼠受损的骨再生。论
老年PDL-MSC龛再生缺陷可逆性及受外源性调节的基础
微环境,这一提议的发现可能为基于Del-1的新方法铺平道路
恢复雀巢功能,从而在老年时增强牙周骨再生。
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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Georgios Hajishengallis其他文献
Georgios Hajishengallis的其他文献
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{{ truncateString('Georgios Hajishengallis', 18)}}的其他基金
Trained innate immunity and periodontitis-associated comorbidities
训练有素的先天免疫和牙周炎相关合并症
- 批准号:
10328655 - 财政年份:2022
- 资助金额:
$ 33.42万 - 项目类别:
Trained innate immunity and periodontitis-associated comorbidities
训练有素的先天免疫和牙周炎相关合并症
- 批准号:
10551226 - 财政年份:2022
- 资助金额:
$ 33.42万 - 项目类别:
IL-22, Immune Plasticity, and Autotherapy in the Periodontium
IL-22、免疫可塑性和牙周组织自体疗法
- 批准号:
10369593 - 财政年份:2020
- 资助金额:
$ 33.42万 - 项目类别:
IL-22, Immune Plasticity, and Autotherapy in the Periodontium
IL-22、免疫可塑性和牙周组织自体疗法
- 批准号:
10577869 - 财政年份:2020
- 资助金额:
$ 33.42万 - 项目类别:
IL-22, Immune Plasticity, and Autotherapy in the Periodontium
IL-22、免疫可塑性和牙周组织自体疗法
- 批准号:
10116365 - 财政年份:2020
- 资助金额:
$ 33.42万 - 项目类别:
Aging and dysfunction of progenitor niches: Role of Del-1
祖细胞生态位的衰老和功能障碍:Del-1 的作用
- 批准号:
10312010 - 财政年份:2020
- 资助金额:
$ 33.42万 - 项目类别:
Neutrophil homeostasis and periodontitis: Novel concepts and treatments
中性粒细胞稳态和牙周炎:新概念和治疗
- 批准号:
9357605 - 财政年份:2016
- 资助金额:
$ 33.42万 - 项目类别:
Neutrophil homeostasis and periodontitis: Novel concepts and treatments
中性粒细胞稳态和牙周炎:新概念和治疗
- 批准号:
9974997 - 财政年份:2016
- 资助金额:
$ 33.42万 - 项目类别:
Local endogenous regulators of functional immune plasticity in the periodontium
牙周组织功能性免疫可塑性的局部内源性调节因子
- 批准号:
9160246 - 财政年份:2016
- 资助金额:
$ 33.42万 - 项目类别:
Local endogenous regulators of functional immune plasticity in the periodontium
牙周组织功能性免疫可塑性的局部内源性调节因子
- 批准号:
10449323 - 财政年份:2016
- 资助金额:
$ 33.42万 - 项目类别:
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