A transcriptomics-guided drug target discovery strategy identifies receptor ligands for lung regeneration

Area of Science:

• Pulmonary Medicine
• Regenerative Medicine
• Pharmacology

Background:

• Chronic obstructive pulmonary disease (COPD) involves defective tissue repair, lacking effective pharmacological treatments.
• Alveolar epithelial progenitor cells are crucial for lung repair but are impaired in COPD.

Purpose of the Study:

• To identify druggable targets for enhancing tissue repair in COPD using a transcriptomics-guided approach.
• To evaluate the therapeutic potential of identified targets in restoring lung function in COPD models.

Main Methods:

• Transcriptomics-guided drug target discovery using COPD gene signatures and mouse models.
• Functional screening of targets in lung organoids and in vivo models.
• Single-cell RNA sequencing to analyze signaling pathways in alveolar epithelial progenitor cells.

Main Results:

• Identified EP and IP prostanoid receptor ligands as having significant regenerative potential.
• Demonstrated that prostaglandin E2 or prostacyclin mimetics restore cigarette smoke-induced defects in alveolar epithelial progenitors.
• Revealed differential expression of circadian clock and cell cycle/apoptosis pathways in COPD alveolar progenitor cells.

Conclusions:

• Targeting EP and IP receptors offers a promising therapeutic strategy for promoting lung tissue repair in COPD.
• Prostaglandin-based therapies can potentially reverse COPD-related damage to alveolar epithelial progenitors.
• Understanding pathway dysregulation in COPD progenitor cells informs future regenerative medicine approaches.