Loss of progenitor function accelerates lung aging

祖细胞功能丧失加速肺部衰老

基本信息

  • 批准号:
    10579157
  • 负责人:
  • 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
  • 起止时间:
    2023-06-15 至 2028-02-29
  • 项目状态:
    未结题

项目摘要

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.
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

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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SUSAN M MAJKA其他文献

SUSAN M MAJKA的其他文献

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{{ truncateString('SUSAN M MAJKA', 18)}}的其他基金

Mesenchymal Vascular Progenitor Depletion Promotes Lung Aging and Susceptibility to Emphysema
间充质血管祖细胞耗竭促进肺衰老和肺气肿易感性
  • 批准号:
    10353622
  • 财政年份:
    2022
  • 资助金额:
    $ 69.86万
  • 项目类别:
Mesenchymal Vascular Progenitor Depletion Promotes Lung Aging and Susceptibility to Emphysema
间充质血管祖细胞耗竭促进肺衰老和肺气肿易感性
  • 批准号:
    10542770
  • 财政年份:
    2022
  • 资助金额:
    $ 69.86万
  • 项目类别:
Loss of progenitor function accelerates lung aging
祖细胞功能丧失加速肺部衰老
  • 批准号:
    10426410
  • 财政年份:
    2021
  • 资助金额:
    $ 69.86万
  • 项目类别:
Role of Lung MSC in Emphysema
肺间充质干细胞在肺气肿中的作用
  • 批准号:
    10153854
  • 财政年份:
    2019
  • 资助金额:
    $ 69.86万
  • 项目类别:
Role of Lung MSC in Emphysema
肺间充质干细胞在肺气肿中的作用
  • 批准号:
    9705978
  • 财政年份:
    2019
  • 资助金额:
    $ 69.86万
  • 项目类别:
Role of Lung MSC in Emphysema
肺间充质干细胞在肺气肿中的作用
  • 批准号:
    9898030
  • 财政年份:
    2019
  • 资助金额:
    $ 69.86万
  • 项目类别:
Role of Lung MSC in Emphysema
肺间充质干细胞在肺气肿中的作用
  • 批准号:
    8848878
  • 财政年份:
    2013
  • 资助金额:
    $ 69.86万
  • 项目类别:
Role of Lung MSC in Emphysema
肺间充质干细胞在肺气肿中的作用
  • 批准号:
    8599945
  • 财政年份:
    2013
  • 资助金额:
    $ 69.86万
  • 项目类别:
Role of Lung MSC in Emphysema
肺间充质干细胞在肺气肿中的作用
  • 批准号:
    8704827
  • 财政年份:
    2013
  • 资助金额:
    $ 69.86万
  • 项目类别:
Induced pluripotent stem cell therapy for lipodystrophy
诱导多能干细胞治疗脂肪营养不良
  • 批准号:
    8542832
  • 财政年份:
    2012
  • 资助金额:
    $ 69.86万
  • 项目类别:

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