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 chemical 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 (e.g. cyp1a1).
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 cytoprotection in cell culture and in vivo to liver injury induced by ER/oxidative stressors. 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 cyp1a1 expression and does not regulate xenobiotic metabolism, consequently these two AhR target genes exhibit mutually exclusive agonist-specific transcriptional responsiveness with distinct physiological consequences.
Agonist specific dichotomy
We study involvement of the chromatin architecture, remodeling, histone post-translational modifications, role of chromatin modification readers, writers and erasers in agonist-specific differential gene regulation by AhR. We utilize specialized LC-MS/MS, chromatin immunoprecipitation, CRISPR-CAS9 gene editing, single cell multiome sequencing techniques in mammalian cell lines and in vivo models.
Characterizing function of stanniocalcin 2
Stanniocalcin 2 (stc2), an AhR target gene is induced in response to the cinnabarinic acid. Stc2 is a secreted, homodimeric glycoprotein which regulates plethora of 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 MASLD, diabetes and obesity using next generation RNA sequencing and high-throughput RNA interference screening methodologies.
Cinnabarinic acid as a pre-clinical therapeutic candidate
We are performing cutting-edge pre-clinical research to characterize role of cinnabarinic acid as a novel therapeutics against alcoholic liver disease (ALD) as well as metabolic dysfunction-associated steatotic liver disease (MASLD) models.
The quest for novel AhR ligands
We are collaborating with medicinal and organic chemists to perform high-throughput screening in order to idenfity novel AhR ligands. Identification of such candidate(s) will decipher role of AhR as a novel drug target for plethora of liver and metabolic diseases.