Regulation of lipid metabolism in pulmonary Type 2 cells

肺2型细胞脂质代谢的调节

基本信息

  • 批准号:
    10542430
  • 负责人:
  • 金额:
    $ 56.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-12-20 至 2026-11-30
  • 项目状态:
    未结题

项目摘要

Surfactant insufficiency compromises pulmonary compliance and respiratory function in multiple pulmonary pathologies. Our understanding of surfactant metabolism in adult pulmonary disease is very limited and this restricts the potential for therapeutic targeting. In this project, we have generated a new genetic model of surfactant insufficiency in adult disease by deleting the low-density lipoprotein receptor related protein 1 (LRP1) specifically in surfactant producing type 2 cells (AEC2). LRP1 functions as lipoprotein receptor and extracellular protease clearing receptor and it is associated with decreased respiratory function in patients with COPD and pulmonary arterial hypertension. Studies in our generated cell line of LRP1 knockdown AEC2 (LRP1 KD) and tamoxifen-inducible AEC2-specific LRP1 knockout mice (SPC-LRP1-/-) show that LRP1 is required to maintain surfactant lipid secretion and intracellular lipid homeostasis to ensure optimal pulmonary compliance and respiratory function. We hypothesize that LRP1 controls surfactant metabolism in AEC2 and we will study the regulatory mechanisms. In Aim 1 we will decipher the mechanism of action of LRP1 at the membrane level in AEC2 and its regulation of the lipid source for surfactant synthesis in AEC2. In Aim 2 we will investigate the epithelial to mesenchymal cross talk and the role of LRP1 in the progressive decline in lung function during profibrotic challenges and molecular mechanisms responsible. We will attempt a new therapeutic approach to stop the decline. This proposal is innovative conceptually and technically. The role of AEC2 lipid metabolism during adult pulmonary disease is unknown. LRP1 regulates many cellular functions through lipid metabolism in different tissues and our study shows that it also regulates pulmonary function through surfactant lipid metabolism. In addition, we use novel techniques that include inducible and cell-specific genetic knockout models in vivo lipid tracing and -omics analysis. Surfactant homeostasis enables basic pulmonary function, but the regulation of surfactant homeostasis in adult disease is very little understood. The significance of this research is further underscored by the fact that surfactant lipid is altered in multiple pulmonary pathologies, including the most prevalent ones.
表面活性物质不足损害肺顺应性和多肺呼吸功能

项目成果

期刊论文数量(0)
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Itsaso Garcia-Arcos其他文献

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{{ truncateString('Itsaso Garcia-Arcos', 18)}}的其他基金

Regulation of lipid metabolism in pulmonary Type 2 cells
肺2型细胞脂质代谢的调节
  • 批准号:
    10367413
  • 财政年份:
    2021
  • 资助金额:
    $ 56.63万
  • 项目类别:
Regulation of lipid metabolism in pulmonary Type 2 cells
肺2型细胞脂质代谢的调节
  • 批准号:
    10002619
  • 财政年份:
    2019
  • 资助金额:
    $ 56.63万
  • 项目类别:

相似海外基金

Interstitial lung diseases (ILD) due to disturbed processing and function of the lipid transporter ABCA3 as a result of mutations in the ABCA3 gene
由于 ABCA3 基因突变,脂质转运蛋白 ABCA3 的加工和功能受到干扰,导致间质性肺疾病 (ILD)
  • 批准号:
    226491218
  • 财政年份:
    2012
  • 资助金额:
    $ 56.63万
  • 项目类别:
    Research Grants
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