Research
The liver undergoes a lifetime of physiological and environmental challenges that can result in chronic liver disease. The Integrative Biology of Advanced Liver Disease Laboratory focuses on several critical aspects of chronic liver disease, including the:
- Mechanisms underlying alcoholic liver disease.
- Interaction between fibrosis and inflammation.
- Role of hepatic stellate cells and endothelial cells in hepatic pathology.
By employing single-cell transcriptomics, spatial transcriptomics and spatial epigenomics, we are comprehensively mapping the liver's cellular and molecular landscape in both healthy and diseased states with unprecedented resolution. These methodologies allow us to identify novel cell states, chromatin accessibility patterns and transcriptional programs within their native tissue context, thus providing new insights into liver pathology and disease conditions, as detailed below:
- Alcoholic liver disease. Alcoholic liver disease is a significant cause of liver cirrhosis and a major contributor to global liver-related mortality. Our program examines various aspects of alcoholic liver disease, including the identification of novel genes and cell type-specific transcriptional responses to alcohol-induced injury. By integrating single-cell RNA sequencing and spatial transcriptomics, we analyze the heterogeneity of hepatocyte and nonparenchymal cell responses in both early and advanced stages of the disease. Furthermore, the application of spatial epigenomics enables us to profile chromatin accessibility across distinct hepatic zones, uncovering how alcohol exposure modifies gene regulation in situ. These findings are applied to clinical settings through treatment trials, biomarker discovery and the development of prognostic models.
- Nonparenchymal liver cell biology. Nonparenchymal cells, including hepatic stellate cells, liver sinusoidal endothelial cells and resident immune cells, significantly contribute to liver fibrosis, inflammation and portal hypertension. Despite representing a minority of liver cell types, their spatial distribution and activation dynamics are essential for disease progression. By employing single-cell multi-omics, spatial transcriptomics and spatially resolved epigenomic profiling, we elucidate the interactions between these cells and hepatocytes during fibrogenesis. This methodology allows us to identify zonated epigenetic states and gene regulatory networks that drive pathological activation, thus providing novel therapeutic targets based on spatial context.
- Novel therapies for portal hypertension. Portal hypertension, a life-threatening complication of cirrhosis, is driven by altered cellular signaling and matrix remodeling in the hepatic vasculature. Spatial epigenomics allows us to define how chromatin landscapes and regulatory accessibility shift across fibrotic zones, revealing region-specific drivers of vascular tone, inflammation and fibrosis. In parallel, we are examining how biomolecular condensates — phase-separated nuclear or cytoplasmic compartments — contribute to the spatial organization of gene regulation and signaling in cells under mechanical and inflammatory stress. Dysregulated condensate formation may act as a rheostat for transcriptional control in fibrotic niches, influencing portal pressure through localized activation of fibrogenic and vasoconstrictive programs. These multidimensional insights inform the development of spatially targeted and condensate-aware therapies to modulate portal pressure and reverse architectural distortion in cirrhotic livers.