Lungs can repair themselves after injury, but when damage is repeated, that repair process goes wrong and turns into scar tissue—a condition called fibrosis. This matters because lung fibrosis is a progressive, often fatal disease with no cure. The researchers have discovered a new type of cell, called a Damage-Associated Transient Progenitor (DATP), that appears during normal lung healing but accumulates and fails to mature properly under chronic inflammation. They want to understand exactly how these cells and their surrounding niche environment shift from regeneration to disease. If this work succeeds, it could identify drug targets that redirect DATPs back toward healthy repair, potentially preventing or treating fibrosis. The project is fundamental science—it will map the cellular conversations, gene activity, and epigenetic changes that govern lung regeneration at single-cell resolution. Similar foundational work on stem cell niches has already led to therapies for blood and skin disorders. Deeper knowledge of how regeneration derails could eventually change how doctors treat chronic lung diseases, but that application is years away.
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Lungs possess a remarkable regenerative capacity by dynamic multicellular responses following injury. However, chronic damage makes these responses persistent, leading to fibrosis. We will define the mechanisms by which productive regeneration programmes are diverted to disease remodelling, with the ultimate goal of uncovering therapeutic strategies that can treat or prevent lung fibrosis. We recently identified Damage-Associated Transient Progenitors (DATPs), a functional mediator of alveolar stem cell differentiation, emerging during lung regeneration. Notably, chronic inflammation leads to accumulation of DATPs displaying defective differentiation, resulting in impaired alveolar regeneration. We aim to identify strategies to target DATPs in chronic injury by dissecting changes in them and their niche environments. Specifically, we will define (1) key DATP-niche interactions during different phases of regeneration, and how to these evolve during disease progression utilising a novel niche-labelling system; (2) transcriptional and epigenetic changes mediating damage-associated reprogramming following injury at single-cell resolutions, and key signalling modules conferring lineage flexibility of stem/niche cells; (3) conserved regenerative programmes and potential therapeutic targets in preclinical 3D human lung disease models we have developed. Our work will provide fundamental insights into defining the cellular and molecular basis of lung regeneration as well as identifying selective therapeutic targets in lung diseases.
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