Research Areas

Type 2 alveolar epithelial cells (AT2s) function as stem cells essential for maintaining and repairing the alveolar epithelium. In IPF, AT2 cells become exhausted and exhibit impaired renewal capacity. No therapies directly restore AT2 progenitor function. Our work seeks to define the cellular and molecular mechanisms that drive AT2 stem cell exhaustion across aging, chronic injury and fibrotic progression. Using single-cell transcriptomics and lineage-resolved multi-omics, we have uncovered disruptions in progenitor lineage dynamics, altered epithelial differentiation trajectories, and epigenetic and transcriptional programs that trap AT2s into dysfunctional transitional states. We aim to delineate how aging, injury response pathways and gene-regulatory networks converge to impair AT2 stemness, limit effective epithelial repair and promote progressive fibrosis.

Building on these findings, we investigate how altered metabolic programs destabilize AT2 progenitor function. Single-cell and bulk multi-omics reveal coordinated defects in amino acid, metal ion (especially zinc), and metabolite transporters; dysregulated lipid metabolism—including phosphatidylcholine synthesis pathways; impaired NAD⁺ metabolism; aberrant retinoid signaling; and elevated aldehyde dehydrogenase activity. These abnormalities converge on mitochondrial dysfunction, driving oxidative stress and metabolic insufficiency that reinforce transitional AT2 states. To dissect these mechanisms, we integrate lineage tracing, 3D organoid assays, transporter-specific gene deletions in mice in vivo, single-cell multi-omics, and comprehensive metabolic and mitochondrial functional analyses to define how metabolic circuit failure alters AT2 fate decisions and progenitor plasticity.

Because AT2 progenitor failure is a root-cause event in IPF pathogenesis, our therapeutic strategy focus is on restoring AT2 regenerative capacity. We have identified several critical molecular signals that regulate AT2 stem cell function, including WNT signaling and transcriptional programs governing AT2 fate. To translate these insights, we are developing CRISPR-mediated, expression-based, high-content screening systems targeting these pathways. Protein structure modeling and molecular docking guide the design and optimization of candidate inhibitors or activators, which are then validated using physiological and functional assays in primary human and mouse AT2 systems. Our long-term goal is to deliver effective, mechanism-based therapies that correct AT2 stem cell dysfunction and transform outcomes for patients with progressive pulmonary fibrosis.