# Epithelial-Mesenchymal Interactions in Pulmonary Fibrosis and Chronic Allograft Dysfunction (CLAD)

> **NIH NIH P01** · CEDARS-SINAI MEDICAL CENTER · 2022 · $2,368,307

## Abstract

ABSTRACT
This application is a renewal for the P01 Program Project Grant “Host Factors in Regulation of Inflammatory and
Fibroproliferative Lung Disease”. This was originally awarded with Dr. Paul Noble as the overall PI at Duke
University in 8/12. The original application consisted of 3 overall projects, Project 1 (Dr. P. Noble), Project 2 (Dr.
Jo Rae Wright, transferred to Dr. Barry Stripp), and Project 3 (Dr. Monica Kraft). Starting in January, 2013 upon
moving Dr. Noble and Dr. Stripp’s research programs to CSMC, we initiated a collaboration with Dr. John
Belperio at UCLA. The unifying theme of this Program Project Grant application is that crosstalk between the
lung epithelium and underlying mesenchyme determines homeostasis versus disease in both pulmonary fibrosis
and CLAD. The overarching hypothesis for this application is that both IPF and CLAD develop in
response to epithelial cell dysfunction AND progenitor cell failure. A fascinating emerging biology is the
relationship between the distal conducting airway epithelium and the distal alveolar epithelium. It is our
contention that CLAD develops from a failure of conducting distal airway progenitor cells and IPF from distal
alveolar epithelial cell failure. However, the loss of progenitor cell function in one compartment may well influence
the other compartment. In response to the loss of epithelial cell homeostasis, there is activation and recruitment
of a destructive mesenchymal cell population that takes on some features of metastasizing cancer cells, i.e., the
ability to invade extracellular matrix. The final reason for the evolution in the application is the investigative team.
We have assembled a team of investigators that have generated new ideas in lung biology, pioneered and
partnered to achieve state of the art tools to address these new ideas and have a track record of success in both
mechanistic animal studies as well as utilizing human tissue samples to advance our understanding of the
pathogenesis of IPF and CLAD. In this Program, we propose a model for the initiation and perpetuation of fibrosis
that emanates from progenitor cell dysfunction in the conducting airway epithelium (multiple progenitor cell types
including club cells) in the case of CLAD, and the alveolar epithelium (alveolar type 2 cell- AT2 or AEC2) in the
case of IPF leading to innate immune cell activation and the recruitment of a mesenchymal phenotype that is
destructive and invasive. We have identified some common features in the pathobiology of CLAD and IPF as
well as unique aspects. The common themes include the recruitment of an invasive fibroblast phenotype as
defined by the ability to invade extracellular matrix (Project 1 – Noble) and the interplay between p53 and IL-22
in regulating bronchiolar epithelial homeostasis (Project 2 – Stripp and Project 3 – Belperio).

## Key facts

- **NIH application ID:** 10450037
- **Project number:** 5P01HL108793-10
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Paul Wesley Noble
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,368,307
- **Award type:** 5
- **Project period:** 2012-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450037

## Citation

> US National Institutes of Health, RePORTER application 10450037, Epithelial-Mesenchymal Interactions in Pulmonary Fibrosis and Chronic Allograft Dysfunction (CLAD) (5P01HL108793-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10450037. Licensed CC0.

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