# Project 1: Mechanisms of Early Disease Progression in FPF

> **NIH NIH P01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $357,056

## Abstract

PROJECT SUMMARY
Although there has been substantial progress over the past decade in deciphering the pathobiology of
progressive pulmonary fibrosis (PF), a large knowledge gap exists regarding the pre-clinical stages of the
disease. To address this need, we propose to leverage our ongoing cohort study of asymptomatic relatives of
patients with familial PF (FPF) in order to define critical mechanisms driving early disease progression and
develop better biomarkers of pre-clinical PF. In this At-Risk for FPF cohort study, 22% of subjects have
detectable interstitial lung abnormalities (ILA) on high resolution CT scanning (HRCT) at study enrollment and
many of these individuals with ILA have evidence of progression during follow-up. In addition to extensive
genotype and phenotype information collected on subjects enrolled in this cohort, we recently performed
single-cell RNA-sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) from 49 subjects in
this cohort and found that transcriptional profiles of several subsets of immune cells, including monocytes and
lymphocytes (T and B cell subsets), differ based on the presence or absence of ILA on HRCT. For example,
we identified a subset of CD14+ monocytes that was over-represented in subjects with ILA on HRCT and
demonstrated gene expression profile enrichment for growth factor and cytokine signaling pathways. We then
determined that PBMCs from subjects with clinical PF undergoing scRNA-seq contained a prominent CD14+
monocyte sub-cluster with a similar transcriptomic profile, thus supporting the potential biological relevance of
this approach. In addition, we measured DNA methylation patterns in PBMCs using the DNAge platform and
found that At-Risk subjects had increased DNAge compared to chronological age, which was highest in
individuals with ILA on HRCT. Overall, we are poised to transform our current understanding of pre-clinical PF
by continuing to study this unique cohort. Proposed studies will test the hypothesis that integration of
transcriptomic profiling, genetic/epigenetic phenotyping, and HRCT imaging will improve understanding of early
disease mechanisms and enable prediction of pre-clinical progression of PF. Specific aims are to: 1) detect
transcriptomic biomarkers of pre-clinical disease in a cohort of subjects at-risk for FPF, 2) identify cellular
signatures of pre-clinical disease in the lungs of subjects at-risk for FPF, and 3) integrate transcriptomic
profiling with measures of “epigenetic age”, genetic susceptibility, and telomere length to identify critical
features of early disease activity in subjects at-risk for FPF. By integrating data obtained in this Project with
information generated across the Program, we will determine mechanisms of pre-clinical FPF and optimize
biomarkers for predicting early disease progression.

## Key facts

- **NIH application ID:** 10846186
- **Project number:** 1P01HL172729-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Timothy S. Blackwell
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $357,056
- **Award type:** 1
- **Project period:** 2024-09-17 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846186

## Citation

> US National Institutes of Health, RePORTER application 10846186, Project 1: Mechanisms of Early Disease Progression in FPF (1P01HL172729-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10846186. Licensed CC0.

---

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