Overview of our Research Projects
Research Focus
Our research is focused on studying pathophysiological and pharmacological role of the hepatic Aryl hydrocarbon Receptor (AhR). AhR is a ubiquitous, ligand-mediated basic helix-loop-helix (bHLH) transcription factor in the Per/Arnt/Sim (PAS) domain protein family. It regulates adaptive and toxic responses to a variety of environmental pollutants, including polycyclic aromatic hydrocarbons and halogenated aromatic hydrocarbons - most notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin). In a canonical pathway, upon ligand binding AhR dissociates from chaperonins, translocate to the nucleus, forms a heterodimer with Aryl hydrocarbon Receptor nuclear translocator (Arnt), and binds to Xenobiotic Response Elements (XRE, GCGTG motif) present in the promoter region of many detoxification genes, which code for the phase I and II xenobiotic metabolic enzymes including members of the cytochrome P450 superfamily.
We recently identified tryptophan catabolite, cinnabarinic acid (CA) as an endogenous AhR agonist capable of activating expression of AhR target gene, stanniocalcin 2 (Stc2). This finding is noteworthy as CA-induced AhR-mediated stc2 upregulation confers protection against alcoholic liver disease and metabolic dysfunction- associated steatohepatitis. Additionally, Stc2 induction exhibits agonist specificity, meaning that CA but not TCDD, induces stc2 expression through an XRE-driven mechanism. Whereas, CA in contrast to TCDD does not trigger phase I and II enzyme expression and does not regulate xenobiotic metabolism. This results in agonist-specific differential gene regulation and signaling by AhR with distinct pathophysiological outcomes.
Agonist specific dichotomy by AhR
We study involvement of epigenetic modifications, chromatin architecture, and remodeling in agonist-specific differential gene regulation by AhR. We utilize specialized CRISPR-CAS9 gene editing, proteomics, chromatin immunoprecipitation and single cell multiome sequencing techniques in mammalian cell lines and in vivo models.
Characterizing function of novel AhR target genes
Stanniocalcin 2 (Stc2), an AhR target gene is induced in response to novel AhR agonist, cinnabarinic acid. Stc2 is a secreted glycoprotein which regulates multiple biological processes including hepatic triglyceride metabolism, cell proliferation and apoptosis, inflammation, oxidative stress, tumorigenesis in an autocrine and/or paracrine manner. We are currently analyzing physiological as well as pathological role of Stc2 in liver and metabolic diseases.
Cinnabarinic acid as a pre-clinical therapeutic candidate against MASLD/MASH
We are performing cutting-edge pre-clinical research to characterize role of cinnabarinic acid as a novel therapeutics against alcoholic liver disease and metabolic dysfunction-associated steatotic liver disease models.
The quest for novel AhR ligands
We are collaborating with medicinal and organic chemists to synthesize, identify, and characterize novel AhR ligands. Identification of such candidate(s) will decipher role of AhR as a novel drug target against liver and metabolic diseases.