Mechanisms of Alveolar Homeostasis, Injury, Regeneration, and Fibrosis

肺泡稳态、损伤、再生和纤维化的机制

基本信息

项目摘要

PROJECT SUMMARY Acute and chronic parenchymal lung diseases, such as the acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis (IPF), are associated with significant morbidity and mortality. Therapies are limited, largely due to our incomplete understanding of disease pathogenesis. These diseases arise from injury to the alveolar epithelium with ineffectual regeneration. In accordance with the NIH mission to “seek fundamental knowledge about the nature…of living systems and apply that knowledge to enhance health”, we aim to identify mechanisms by which alveolar homeostasis is maintained, disrupted during injury, and restored during physiologic regeneration and how these processes go awry in the pathogenesis of ARDS and IPF. The normal alveolus consists of alveolar type 2 epithelial cells (AEC2s) and AEC1s, which form a tight barrier, with quiescent fibroblasts and alveolar macrophages. The molecular mechanisms of cell-cell crosstalk that maintain alveolar quiescence during homeostasis are poorly understood. During lung injury, AECs die. Severe acute injury results in barrier permeability, leading to ARDS; clinical recovery requires epithelial regeneration. In IPF, repetitive epithelial injury with impaired regeneration begets fibrosis. However, the mechanisms underlying physiologic regeneration and how it is impaired in the pathogenesis of IPF are incompletely understood. AEC2s are the primary progenitor responsible for physiologic alveolar regeneration. AEC2s proliferate, then differentiate into AEC1s. We and others have identified mechanisms of AEC2 proliferation. Moreover, we were the first to identify a novel transitional cell state transiently assumed by regenerating AEC2s before differentiating into AEC1s. We also found that transitional cells persist in pulmonary fibrosis, suggesting that persistence of transitional cells may be the critical regenerative defect driving fibrosis. However, the mechanisms that induce AEC2s to assume the transitional state and transitional cells to differentiate into AEC1s during physiologic regeneration and by which transitional cells persist and promote fibrosis in IPF are unknown. Here, we will explore the mechanisms of alveolar cell-cell crosstalk that maintain homeostasis and promote physiologic regeneration and how these mechanisms go awry in ARDS and fibrosis. We will use lineage tracing combined with AEC2-specific inducible gene knockout in mouse models of homeostasis, injury, physiologic regeneration, and fibrosis. Cultured human and murine AECs will be used to dissect mechanism. The proposed work will fill fundamental gaps in our understanding of alveolar homeostasis and physiologic and pathologic regeneration and overcome critical barriers to the development of novel therapies for ARDS and IPF. The funding will also support the pursuit of new lines of investigation and the dedication of appropriate time and energy into collaborations, professional service, and mentorship.
项目总结

项目成果

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Rachel Lynne Zemans其他文献

Rachel Lynne Zemans的其他文献

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{{ truncateString('Rachel Lynne Zemans', 18)}}的其他基金

Mechanisms of Alveolar Homeostasis, Injury, Regeneration, and Fibrosis
肺泡稳态、损伤、再生和纤维化的机制
  • 批准号:
    10348551
  • 财政年份:
    2022
  • 资助金额:
    $ 89.84万
  • 项目类别:
Role of TGFβ/BMP Antagonism in Regeneration of the Alveolar Epithelium After Lung Injury
TGFβ/BMP 拮抗作用在肺损伤后肺泡上皮再生中的作用
  • 批准号:
    10165810
  • 财政年份:
    2020
  • 资助金额:
    $ 89.84万
  • 项目类别:
Mechanisms of Repair of the Alveolar Epithelium after Lung Injury
肺损伤后肺泡上皮的修复机制
  • 批准号:
    9898424
  • 财政年份:
    2016
  • 资助金额:
    $ 89.84万
  • 项目类别:
Mechanisms of Repair of the Alveolar Epithelium after Lung Injury
肺损伤后肺泡上皮的修复机制
  • 批准号:
    9247828
  • 财政年份:
    2016
  • 资助金额:
    $ 89.84万
  • 项目类别:
Mechanisms of alveolar epithelial repair in lung injury
肺损伤中肺泡上皮修复机制
  • 批准号:
    9130419
  • 财政年份:
    2015
  • 资助金额:
    $ 89.84万
  • 项目类别:
Role of Beta-catenin in Epithelial Repair in Acute Lung Injury
β-连环蛋白在急性肺损伤上皮修复中的作用
  • 批准号:
    7953459
  • 财政年份:
    2010
  • 资助金额:
    $ 89.84万
  • 项目类别:
Role of Beta-catenin in Epithelial Repair in Acute Lung Injury
β-连环蛋白在急性肺损伤上皮修复中的作用
  • 批准号:
    8286942
  • 财政年份:
    2010
  • 资助金额:
    $ 89.84万
  • 项目类别:
Role of Beta-catenin in Epithelial Repair in Acute Lung Injury
β-连环蛋白在急性肺损伤上皮修复中的作用
  • 批准号:
    8120783
  • 财政年份:
    2010
  • 资助金额:
    $ 89.84万
  • 项目类别:
Role of Beta-catenin in Epithelial Repair in Acute Lung Injury
β-连环蛋白在急性肺损伤上皮修复中的作用
  • 批准号:
    8496866
  • 财政年份:
    2010
  • 资助金额:
    $ 89.84万
  • 项目类别:

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肺泡单核吞噬细胞在急性呼吸窘迫综合征中的作用
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    402473
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    2019
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肺泡单核吞噬细胞在急性呼吸窘迫综合征中的作用
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    10231127
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急性呼吸窘迫综合征对人肺泡巨噬细胞极性的影响
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    9393863
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    2018
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    $ 89.84万
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    9294401
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    9219006
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    366631
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