# The role of the epithelial-derived chemokine, CXCL12, in Idiopathic Pulmonary Fibrosis

> **NIH NIH F32** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $75,930

## Abstract

Project Summary/Abstract:
Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrosing lung disease for which there is no cure. IPF is
associated with aging and will likely become more common as our population ages. The pathophysiology of
IPF remains incompletely understood, but the alveolar epithelium, specifically the senescent alveolar
epithelium, has recently been implicated in this disease. Telomeres are DNA and protein caps on the ends of
chromosomes. Short telomeres are a known risk factor for IPF, and mutations in telomere maintenance genes
cause IPF. In the setting of telomere dysfunction, alveolar epithelial cells (AECs) rather than dying,
preferentially become senescent. Senescent AECs have been shown to secrete pro-survival and pro-fibrotic
proteins. This is known as the senescence-associated secretory phenotype (SASP). Multiple SASP proteins
have been shown to be capable of inducing their own secretion through autocrine (feed-forward) pathways and
to also signal in the traditional paracrine fashion to bystander, non-senescent cells. CXCL12, a SASP protein,
has previously been shown to be capable of both autocrine and paracrine signaling in an AEC-like cell line, but
the downstream transcriptional and proteomic consequences have not been fully explored. CXCL12 has also
been shown to play an important role in lung morphogenesis, but the major cell-type of origin of CXCL12 is not
known. The main objective of this proposal is to determine the role of CXCL12 as an autocrine and paracrine
mediator originating from a senescent alveolar epithelium and whether loss of CXCL12 signaling from the
pulmonary epithelium prevents the fibrotic response. The downstream signals CXCL12 generates on the
alveolar epithelium itself will be explored in depth. Aim 1 will utilize a novel conditionally senescent alveolar
epithelial-like cell line to explore the consequences of autocrine and paracrine CXCL12 signaling onto the
epithelium itself. Aim 2 will seek to determine the function of pulmonary epithelium-derived CXCL12 in a mouse
model of pulmonary fibrosis. The knowledge gained from the completion of these studies may promote further
research into the role of the alveolar epithelium in IPF and influence the allocation of resources toward the
development of CXCL12 pathway-based therapeutics for this disease. Furthermore, this project will provide the
applicant the opportunity to develop expertise in lung epithelial cell biology and immunology. The training plan
will promote acquisition of advanced laboratory skills including flow cytometry, CRISPR/Cas genome editing,
proteomics, and multiple elements of animal modeling. Additionally, didactic courses have been selected to
supplement the hands-on training received and promote the advancement of the applicant’s career. Combined
with close mentoring and the robust research environment at the University of Pittsburgh, this proposal will
support the candidate’s development as an independent physician-scient...

## Key facts

- **NIH application ID:** 9988795
- **Project number:** 1F32HL152503-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Daniel Sullivan
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $75,930
- **Award type:** 1
- **Project period:** 2020-04-16 → 2021-12-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988795

## Citation

> US National Institutes of Health, RePORTER application 9988795, The role of the epithelial-derived chemokine, CXCL12, in Idiopathic Pulmonary Fibrosis (1F32HL152503-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9988795. Licensed CC0.

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