# Regulation of lipid metabolism in pulmonary Type 2 cells

> **NIH NIH R01** · SUNY DOWNSTATE MEDICAL CENTER · 2022 · $562,555

## Abstract

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.

## Key facts

- **NIH application ID:** 10367413
- **Project number:** 1R01HL148774-01A1
- **Recipient organization:** SUNY DOWNSTATE MEDICAL CENTER
- **Principal Investigator:** Itsaso Garcia-Arcos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $562,555
- **Award type:** 1
- **Project period:** 2021-12-20 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367413

## Citation

> US National Institutes of Health, RePORTER application 10367413, Regulation of lipid metabolism in pulmonary Type 2 cells (1R01HL148774-01A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10367413. Licensed CC0.

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