The evolutionary continuum from lung development to homeostasis and repair

Area of Science:

• Evolutionary developmental biology
• Comparative genomics
• Molecular biology

Background:

• Gene regulatory networks (GRNs) provide context for biological processes.
• Evolutionary developmental biology (Evo-Devo) facilitates cross-species GRN comparisons.
• Lung evolution research benefits from integrating developmental and phylogenetic perspectives.

Purpose of the Study:

• To elucidate the role of the parathyroid hormone-related protein (PTHrP) gene regulatory network in lung evolution, development, and disease.
• To explore the continuum from ontogeny to phylogeny, homeostasis, and repair in the context of lung biology.
• To identify novel diagnostic and therapeutic targets for lung fibrosis based on epithelial-mesenchymal crosstalk.

Main Methods:

• Comparative analysis of GRNs across species.
• Functional studies of PTHrP signaling in lung development and repair.
• Investigation of lipofibroblast differentiation and its regulation by Wnt and cAMP pathways.
• Targeting peroxisome proliferator-activated receptor gamma (PPARγ) to prevent fibrosis.

Main Results:

• PTHrP signaling promotes lipofibroblast differentiation by modulating Wnt and cAMP pathways.
• Leptin signaling, downstream of lipofibroblasts, is crucial for alveolar homeostasis and surfactant synthesis.
• Dysfunctional PTHrP signaling leads to lipofibroblast to myofibroblast transdifferentiation, a hallmark of lung fibrosis.
• Targeting PPARγ, a downstream mediator of PTHrP signaling, effectively prevents lung fibrosis in models.

Conclusions:

• The PTHrP GRN is a key regulator in lung evolution, development, and homeostasis.
• Lung repair mechanisms recapitulate developmental and evolutionary processes, involving epithelial-mesenchymal crosstalk.
• Understanding this crosstalk as a recapitulation of ontogeny and phylogeny offers novel therapeutic strategies for lung fibrosis.