# Mechanistic studies of the genetic contribution of desmoplakin to pulmonary fibrosis in alveolar type 2 cells

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $764,263

## Abstract

Project Summary/Abstract
In recent decades, genome-wide association studies (GWAS) have identified genetic variants associated with
a variety of traits and diseases, a critical first step towards understanding the molecular mechanisms that
underlie common health conditions. In many cases, however, the functions of GWAS genes, the mechanisms
and consequences of their dysfunction, or the relevant cell types in which their dysfunction manifests a
clinically significant phenotype remain poorly understood. The GWAS gene DSP encodes a junctional protein
found in desmosomes that provide structural integrity to epithelial cells in tissues that experience mechanical
stress, such as skin, heart, and lung. A variant associated with DSP expression in lung but not other tissues,
rs2076295, has been linked to both pulmonary fibrosis and chronic obstructive pulmonary disease
susceptibility in GWAS. In recent years, we and others have developed protocols to differentiate, mature, and
model disease in human AT2s derived from iPSCs (iAT2s) and in preparation for this proposal we have
adapted this model system to interrogate lung disease-relevant GWAS discoveries. We hypothesize that
reductions in DSP mediated through rs2076295 destabilize desmosomes to regulate AT2 phenotypes through
modulation of Wnt/Tcf signaling either at homeostasis or in the setting of injury that impairs AT2 differentiation
capacity and induces a profibrotic mesenchymal phenotype. To test this hypothesis in this proposal, we will
test the mechanisms through which DSP regulates iAT2 maturation through CRISPR-based knockdown or
overexpression of DSP or its binding partners. We will identify the contribution of reduced DSP expression on
iAT2 transdifferentiation capacity and potential emergence of cells in a transitional state. We will then test the
contribution of DSP to AT2 regenerative capacity and associated fibrotic lung injury in vivo using AT2-specific
Dsp deletions in mice in combination with bleomycin injury. Finally, we will leverage LTRC data to determine
mechanisms through which rs2076295 regulates gene expression and then validate those predictions in
patient iAT2s.

## Key facts

- **NIH application ID:** 10903825
- **Project number:** 5R01HL166407-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** ANDREW A WILSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $764,263
- **Award type:** 5
- **Project period:** 2023-08-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903825

## Citation

> US National Institutes of Health, RePORTER application 10903825, Mechanistic studies of the genetic contribution of desmoplakin to pulmonary fibrosis in alveolar type 2 cells (5R01HL166407-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10903825. Licensed CC0.

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