# Delineating the role of let-7 microRNA on lung AT2 cell homeostasis, alveolar regeneration, and interstitial lung disease

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $515,003

## Abstract

Project Summary
Interstitial lung diseases (ILDs) including Idiopathic Pulmonary Fibrosis (IPF) are associated with significant
morbidity and mortality. Treatment options for patients with ILD are limited by a lack of understanding of the
pathophysiologic mechanisms. Alveolar type 2 (AT2) cells, the main epithelial progenitor stem cell population in
the lung, are critically important in ILD pathophysiology as they regulate surfactant production and operate as
stem cell progenitors for repair of alveoli after injury via generation of alveolar type 1 (AT1) cells. Disruptions to
the DNA, protein, organellar quality control, and cell metabolism have all been hypothesized to underlie AT2-cell
driven ILD. Recent insights on the AT2 cell states and differentiation trajectories led to the discovery of primed
and cycling AT2 (pAT2 and cAT2) cell subpopulation(s) and alveolar differentiation intermediate (ADI) cells,
which convert into AT1 cells during lung injury. However, the global regulatory mechanisms that contribute to
dysregulated AT2 cell homeostasis and the relationship to impaired AT2 progenitor stem cell renewal are not
well understood. In preliminary work, we found that conditional inactivation of let-7 microRNA clusters specifically
in alveolar AT2 cells in mice promotes spontaneous age-dependent parenchymal remodeling with features of
ILD including pronounced septal alveolar thickening, fibroblastic foci with collagen deposition and pronounced
alveolitis. We also found that let-7 promotes hyperplasia of AT2 cells and the appearance of ADI transitional
cells with a cellular senescence profile. Based on transcriptomic data hypothesize that the let-7 family of
microRNAs serves as an essential coordinator of AT2 cell autophagy & lipid homeostasis, progenitor stem cell
renewal, and AT1 differentiation. In this proposal, we will extend these exciting findings to (1) determine how the
let-7 pathway regulates AT2 progenitor stem cell trajectories and cell differentiation dynamics during ILD; (2)
determine how let-7 pathway impairs AT2 cell surfactant homeostasis and contributes to alterations in autophagy
and lipid metabolism during ILD remodeling; and (3) identify mechanism(s) through which let-7 controls AT2 cell
renewal in mice and humans. The project will elucidate a fundamental repair and regeneration process in the
lung and pave the way for new targetable pathways for drug discovery in the context of IPF.

## Key facts

- **NIH application ID:** 10817705
- **Project number:** 5R01HL167814-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Antony Rodriguez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $515,003
- **Award type:** 5
- **Project period:** 2023-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817705

## Citation

> US National Institutes of Health, RePORTER application 10817705, Delineating the role of let-7 microRNA on lung AT2 cell homeostasis, alveolar regeneration, and interstitial lung disease (5R01HL167814-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10817705. Licensed CC0.

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