# Lung Allograft Stem Cell Regeneration and Immune Destruction

> **NIH NIH R00** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2024 · $248,526

## Abstract

PROJECT SUMMARY: End-stage lung disease is the third leading cause of death worldwide. Lung
transplantation is often the only option for patients with advanced lung disease, yet 50% of recipients die within
five years due to the development of chronic lung allograft dysfunction (CLAD). This project seeks to examine
the basis for the loss of region-specific stem cells and impaired airway regeneration, with a long-term goal of
improving cell-based regenerative medicine approaches. We will make use of innovative transgenic ferret
models in our well-established orthotopic lung transplantation model. We will investigate the role of glandular
myoepithelial cells (MECs) in renewing submucosal gland (SMG) cells and generating abnormal surface basal
stem cells (BSCs) in CLAD. We hypothesize that sustained regenerative pressures drive MECs to exit their SMG
stem cell niche to reconstitute surface BSCs with abnormal lineage properties that promote an immune response.
Additionally, this project will determine the regenerative function of KRT7+ glandular duct cells (DCs) during the
progression of CLAD. We hypothesize that the gland duct is a maturation point for MEC stem cells to adopt a
surface BSCs phenotype that is bypassed under sustained regenerative stresses in CLAD. Finally, we will
determine the relationship of antigen-experienced B-cells in promoting alloimmune and autoimmune reactions
against airway stem cells to drive CLAD. We hypothesize that prolonged regeneration of surface BSCs by
reserve MEC stem cells leads to the retention of MEC proteins on the airway surface. This ectopic expression
of self-antigens promotes an autoimmune response against the SMG stem cells niche. Currently, end-stage lung
disease is a significant cause of morbidity. However, we expect that by clarifying the processes that deplete stem
cells in transplanted lungs, we will improve the likelihood of developing long-term objectives of developing
effective stem cell therapies to sustain lung function and resilience to prevent CLAD.

## Key facts

- **NIH application ID:** 11004179
- **Project number:** 4R00HL155843-03
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Thomas J Lynch
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $248,526
- **Award type:** 4N
- **Project period:** 2024-06-14 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11004179

## Citation

> US National Institutes of Health, RePORTER application 11004179, Lung Allograft Stem Cell Regeneration and Immune Destruction (4R00HL155843-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11004179. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*