Project Details
Description
PROJECT SUMMARY
Despite modest improvement in patient outcomes from recent advances in pharmacotherapy targeting
fibrogenic signaling pathways, Idiopathic Pulmonary Fibrosis (IPF) remains a major unsolved clinical problem.
One reason for this is that currently available anti-fibrotic agents slow but do not arrest fibrotic progression. To
fully arrest fibrotic progression, its obligatory drivers need to be identified. We have made several recent
discoveries studying primary cells and ECM from IPF patients that illuminate a path forward toward
understanding mechanisms driving the relentless progression of fibrosis following disease initiation. We
learned that fibrosis progression involves cell-intrinsic/autonomous mechanisms. Cell-autonomous fibrogenicity
was established by our discovery of fibrogenic mesenchymal progenitor cells (MPCs) in the lungs of patients
with IPF and that S100A4 mediates their fibrogenicity. Our data indicate that fibrogenic mesenchymal cells
residing in a fibrogenic ECM is a key driver of fibrotic progression in the human IPF lung. We have recently
discovered that the sentinel morphologic lesion of IPF, the fibroblastic focus, is a polarized structure with an
active fibrotic front that contains IPF MPCs, their transit amplifying progeny and activated macrophages
residing in a hyaluronan (HA)-rich extracellular matrix (ECM) that supports their pathological properties. In
contrast, the core of the fibroblastic focus is a collagen-rich region containing non-cycling myofibroblasts
actively synthesizing and depositing ECM. In this proposal we will: i) examine the role of nuclear, cytoplasmic
and extracellular S100A4 in regulating the fibrogenicity of IPF MPCs and their progeny; ii) define the key
components of the fibrogenic niche microenvironment that regulate S100A4 function; and iii) identify subgroups
of phenotypically distinct MPCs within the fibrogenic niche that cooperate to drive fibrotic progression. Two
Aims are proposed: In Aim 1 we will determine the molecular mechanism by which the HA-CD44 axis regulates
nuclear S100A4 function and MPC self-renewal and identify subgroups of IPF MPCs based on SSE4 and HA
cell surface expression; in Aim 2 we will determine the role of cytoplasmic S100A4 in acquisition of a motile
phenotype as IPF MPCs differentiate to IPF fibroblasts; and examine the role of IPF MPC progeny-derived
extracellular S100A4 in driving fibrotic progression. New knowledge about subgroups of fibrogenic MPCs, the
cells that support them within the active fibrotic front, and fibrogenic signals in the microenvironment; has the
potential to greatly advance the design of therapeutics that fully arrest fibrotic progression and even reverse
established fibrosis.
!
Status | Finished |
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Effective start/end date | 4/1/19 → 3/31/24 |
Funding
- National Heart, Lung, and Blood Institute: $592,286.00
- National Heart, Lung, and Blood Institute: $522,986.00
- National Heart, Lung, and Blood Institute: $604,351.00
- National Heart, Lung, and Blood Institute: $601,271.00
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