Mechanisms governing the physiologic regulation of cell fate: Hypoxia-induced differentiation of neuroendocrine cells from stem cells

细胞命运生理调控机制:缺氧诱导神经内分泌细胞从干细胞分化

基本信息

  • 批准号:
    10633171
  • 负责人:
  • 金额:
    $ 59.82万
  • 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:
    2020-07-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

Project Summary Decades of studies have suggested that pulmonary neuroendocrine cells perform multiple functions including oxygen sensing, mechanotransduction, regulation of pulmonary blood flow, regulation of airway diameter, chemosensation, and most recently the regulation of inflammation. Additionally, increased NE cell abundance has been documented in several respiratory diseases including pulmonary hypertension, neuroendocrine hyperplasia of infancy (NEHI), sudden infant death syndrome, asthma, bronchopulmonary dysplasia, congenital pneumonia, cystic fibrosis, COPD, and congenital diaphragmatic hernia. However, it remains unclear whether these NE cells are a cause of disease or whether they represent a protective regenerative response to injury. Prior research has largely been conducted on neuroendocrine bodies (NEBs) which are clustered NE cells occurring at airway branch points. Herein, we focus on the role of solitary neuroendocrine cells which may represent a distinct population of NE cells that, like NEBs, are increased in diseases associated with NE cell hyperplasia. We provide evidence that hypoxia, frequently encountered in severe lung disease, stimulates neuroendocrine differentiation as a protective response. Using lineage tracing, we will test whether hypoxia-induced NE cells are plastic and capable of differentiating into other cell types following injury. We will also assess whether NE cell hyperplasia is reversible following the restoration of normoxia using a novel airway explant system coupled to long term 2 photon imaging. We hypothesize that hypoxia-dependent neuroendocrine differentiation is mediated through the HIF signaling cascade localized to the basal stem cell compartment, and will test whether airway stem cells possess this oxygen sensing machinery which in turn is responsible for triggering the onset of NE cell differentiation. We will further examine whether HIF signaling independent of hypoxia is required for the normal maintenance of tissue resident NE cells. Using genetic cell ablation, we will assess the functional relevance of hypoxia-induced neuroendocrine differentiation in injury models. We will then test whether the abundant peptide CGRP is a protective neuropeptide that ameliorates hypoxia-induced epithelial injury by promoting progenitor cell proliferation and preventing cell death. To address NE cell heterogeneity, we have identified Tuj1 as an epithelial marker of solitary NE cells that is absent in NEBs. We show that hyperplastic NE cells in Neuroendocrine Hyperplasia of Infancy (NEHI) are positive for this marker. Lastly, we will establish a system for studying human primary airway stem cell differentiation into Tuj1+ solitary NE cells following hypoxia.
项目摘要 几十年的研究表明,肺神经内分泌细胞执行多种功能,包括 氧感测、机械传导、肺血流量的调节、气道直径的调节, 化学感觉,以及最近的炎症调节。此外,NE细胞丰度增加 已被记录在几种呼吸系统疾病中,包括肺动脉高压、神经内分泌 婴儿增生(NEHI),婴儿猝死综合征,哮喘,支气管肺发育不良,先天性 肺炎、囊性纤维化、COPD和先天性腹股沟疝。然而,目前尚不清楚是否 这些NE细胞是疾病的原因,或者它们是否代表对损伤的保护性再生反应。 以前的研究主要是在神经内分泌体(NEB)上进行的,NEB是聚集的NE细胞 发生在气道分支点。在此,我们着重于孤立的神经内分泌细胞的作用, 代表NE细胞的独特群体,与NEB一样,在与NE细胞相关的疾病中增加。 增生 我们提供的证据表明,缺氧,经常遇到的严重肺部疾病,刺激神经内分泌 分化作为一种保护性反应。使用谱系追踪,我们将测试缺氧诱导的NE细胞是否 可塑性,并能在损伤后分化成其他细胞类型。我们还将评估NE细胞是否 使用一种新的气道外植系统, 长期双光子成像。我们假设缺氧依赖的神经内分泌分化是由 通过HIF信号级联定位于基底干细胞室,并将测试气道是否 干细胞具有这种氧感应机制,这反过来又负责触发NE细胞的发作, 分化我们将进一步研究是否HIF信号独立于缺氧是所需的正常 维持组织驻留NE细胞。使用遗传细胞消融,我们将评估以下功能的相关性: 损伤模型中缺氧诱导的神经内分泌分化。然后我们将测试丰富的肽是否 CGRP是一种保护性神经肽,其通过促进祖细胞增殖来改善缺氧诱导的上皮损伤。 细胞增殖和防止细胞死亡。为了解决NE细胞的异质性,我们已经将Tuj1鉴定为 NEB中不存在的孤立NE细胞的上皮标志物。我们发现,增生的NE细胞, 婴儿神经内分泌增生(NEHI)对此标志物呈阳性。最后,我们将建立一个系统, 研究人原代气道干细胞在缺氧后分化为Tuj1+孤立NE细胞。

项目成果

期刊论文数量(1)
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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JAYARAJ RAJAGOPAL其他文献

JAYARAJ RAJAGOPAL的其他文献

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{{ truncateString('JAYARAJ RAJAGOPAL', 18)}}的其他基金

Defining the lineage, mechanisms of maintenance, and function of a new injury-resistant airway epithelial structure: the hillock
定义新的抗损伤气道上皮结构的谱系、维持机制和功能:小丘
  • 批准号:
    10364896
  • 财政年份:
    2022
  • 资助金额:
    $ 59.82万
  • 项目类别:
Defining the lineage, mechanisms of maintenance, and function of a new injury-resistant airway epithelial structure: the hillock
定义新的抗损伤气道上皮结构的谱系、维持机制和功能:小丘
  • 批准号:
    10615044
  • 财政年份:
    2022
  • 资助金额:
    $ 59.82万
  • 项目类别:
Progenitors, Mechanisms of Differentiation, and Functions of Lung M Cells
肺 M 细胞的祖细胞、分化机制和功能
  • 批准号:
    10673927
  • 财政年份:
    2022
  • 资助金额:
    $ 59.82万
  • 项目类别:
Progenitors, Mechanisms of Differentiation, and Functions of Lung M Cells
肺 M 细胞的祖细胞、分化机制和功能
  • 批准号:
    10502088
  • 财政年份:
    2022
  • 资助金额:
    $ 59.82万
  • 项目类别:
Mechanisms governing the physiologic regulation of cell fate: Hypoxia-induced differentiation of neuroendocrine cells from stem cells
细胞命运生理调控机制:缺氧诱导神经内分泌细胞从干细胞分化
  • 批准号:
    10404537
  • 财政年份:
    2020
  • 资助金额:
    $ 59.82万
  • 项目类别:
Mechanisms governing the physiologic regulation of cell fate: Hypoxia-induced differentiation of neuroendocrine cells from stem cells
细胞命运生理调控机制:缺氧诱导神经内分泌细胞从干细胞分化
  • 批准号:
    10204103
  • 财政年份:
    2020
  • 资助金额:
    $ 59.82万
  • 项目类别:
Intercellular communication and cell regulation in airway epithelial ensembles in regeneration and disease
再生和疾病中气道上皮群的细胞间通讯和细胞调节
  • 批准号:
    9770564
  • 财政年份:
    2018
  • 资助金额:
    $ 59.82万
  • 项目类别:
Intercellular communication and cell regulation in airway epithelial ensembles in regeneration and disease
再生和疾病中气道上皮群的细胞间通讯和细胞调节
  • 批准号:
    10240642
  • 财政年份:
    2018
  • 资助金额:
    $ 59.82万
  • 项目类别:
Defining the mechanism of Clara cell dedifferentiation into basal stem cells
定义Clara细胞去分化为基底干细胞的机制
  • 批准号:
    8791271
  • 财政年份:
    2014
  • 资助金额:
    $ 59.82万
  • 项目类别:
Defining the mechanism of Clara cell dedifferentiation into basal stem cells
定义Clara细胞去分化为基底干细胞的机制
  • 批准号:
    8625398
  • 财政年份:
    2014
  • 资助金额:
    $ 59.82万
  • 项目类别:

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