# Project 4:  Defining the Molecular Natural History of Early and Progressive Pulmonary Fibrosis

> **NIH NIH P01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $554,851

## Abstract

PROJECT SUMMARY
The advent of single cell RNA-sequencing (scRNA-seq) revolutionized our ability to study the molecular
mechanisms underlying pulmonary fibrosis (PF). Our group has leveraged this approach to identify novel cell
types and cell states, as well as to characterize the genetic architecture of gene expression in advanced PF.
While this work has made significant impact, it has also raised important questions about the timing and
coordination of disease pathogenesis and pre-clinical progression. Combining advances in imagining based
spatial transcriptomics and a unique set of formalin-fixed, paraffin-embedded transbronchial biopsy samples
from subjects in our At-Risk for Familial PF (FPF) Cohort, we can now characerize and localize molecular and
cellular dysregulation during the earliest phases of disease. In preliminary studies, we performed spatial
transcriptomic analysis of FFPE tissue from a small subset of the At-Risk for FPF Cohort, as well as a larger
cohort of samples from declined donors and late-stage disease. Using these data we quantified cell type
composition across samples and found higher representation of cells that are often depleted in single cell
assays – e.g. AT1, endothelial, and fibroblast cells. Importantly, taking full advantage of the in situ nature of
these data we identified distinct molecular niches using both cell-cell and transcriptional neighborhoods.
Importantly, these approaches were able to distinguish between histologically similar regions with differing
underlying cellular and molecular profiles. Furthermore, we found gene expression differences between
healthy and dysregulated alveolar niches between controls and late stage disease were similar to expression
differences that preceded radiographic disease in the At-Risk for FPF cohort. We hypothesize that disruption of
specialized niche-specific regulatory programs in the distal lung results in a spatially coordinated activation of
multicellular disease amplification programs to mediate the initiation and progression of pulmonary fibrosis. Our
Specific Aims are to: 1) develop a spatially-resolved molecular atlas of pre-clinical FPF, 2) define disease-
stage-specific regulatory mechanisms throughout the natural history of PF, and 3) identify niche-perturbations
which promote and ameliorate disease progression in ex vivo models. Together this study represents a
comprehensive analysis of the molecular and cellular mechanisms underlying PF. We anticipate the results of
these analyses will identify novel therapeutically relevant targets that have immense potential to impact
patients with PF.

## Key facts

- **NIH application ID:** 10846188
- **Project number:** 1P01HL172729-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Nicholas Eli Banovich
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $554,851
- **Award type:** 1
- **Project period:** 2024-09-17 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846188

## Citation

> US National Institutes of Health, RePORTER application 10846188, Project 4:  Defining the Molecular Natural History of Early and Progressive Pulmonary Fibrosis (1P01HL172729-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10846188. Licensed CC0.

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