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

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,牙周炎是一种普遍的炎症性疾病, 破坏牙齿支持组织(牙周组织)。这种增加的易感性可能是由 牙周组织的免疫炎症状态和/或再生潜力的改变。受损 组织再生可以追溯到与年龄相关的间充质干细胞(MSC)生态位的改变, 牙周膜(PDL),窝藏骨祖细胞。Del-1是一种稳态蛋白, 不同的组织驻留细胞:它调节中性粒细胞(内皮细胞衍生的Del-1)的募集, 凋亡中性粒细胞的巨噬细胞源性Del-1,因此Del-1控制细胞凋亡的起始和 炎症消退。其他研究表明,Del-1在PDL中产生,并促进 成骨细胞分化以及诱导新牙槽骨的形成, 实验性牙周炎然而,Del-1表达在老年时严重减少。该项目调查 总的假设是,与衰老相关的Del-1缺乏可能导致 骨生成,从而导致老年牙周骨再生缺陷。这项建议包括: 两个具体的目标,并侧重于相关的动物模型为基础的机制和干预研究,包括 Del-1或其受体β3整联蛋白谱系特异性缺失或过表达的小鼠。在目标1中,建议 Del-1通过其RGD基序作用于成骨细胞系中的β3整合素促进成骨细胞分化 祖先目的二是阐明Del-1在体内调控成骨的机制 此外,还研究了衰老相关的Del-1缺乏对骨再生的影响。也是 提出老年小鼠受损的骨再生可以通过局部施用Del-1逆转。上 老年PDL-MSC龛的再生缺陷是可逆的,并受外源性 微环境,这项建议的发现可能为新的基于Del-1的方法铺平道路 以恢复生态位功能,从而增强老年牙周骨再生。

项目成果

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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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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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