Excessive or sustained hepatocyte apoptosis is an underlying pathology of various acute liver injuries like fulminant hepatitis, ischemia and reperfusion damage, drug induced hepatotoxicity and chronic injuries associated with viral hepatitis, non-alcoholic fatty liver disease and alcoholic liver disease. This proposal is built on my recent observation that the aryl hydrocarbon receptor (AhR) agonist cinnabarinic acid (CA) upregulates expression of AhR target gene, Stanniocalcin 2 (STC2), which plays a crucial cytoprotective role against ER/oxidative stress induced apoptosis in hepatocytes. Moreover, STC2 induction occurs in response to the endogenous AhR agonist cinnabarinic acid, but not the prototypical exogenous AhR agonist 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD).
Specific aim 1 of this application tests the hypothesis that endogenous and exogenous AhR agonists can induce dichotomous signaling cascades with distinct physiological consequences. I will specifically examine mechanism by which CA, but not TCDD, induces STC2 expression responsible for cytoprotection.
Specific aim 2 embarks on genome-wide functional assessment of endogenous AhR agonist CA. This study will particularly identify repertoire of CA regulated AhR target genes using next generation sequencing.
Specific Aim 3 will test the cytoprotective property of CA in vivo in a mouse model of chronic alcohol induced hepatotoxicity.
This aim will address potential of CA as a lead compound in the development of therapeutically useful drugs against liver injury. This research project is integrated with a structured career development plan. The objectives of my career development plan are: 1) To develop an independent research program in AhR biology centered on understanding receptor's role in liver injury and agonist specific AhR signaling. 2) Expand my skill sets by obtaining advanced training in mass spectrometry, next generation sequencing analysis, liver function tests and complementary biochemical techniques. 3) Establish collaborative relationships with researchers in liver diseases, apoptosis, drug development, biophysics and bioinformatics fields. 4) Secure a track record of high quality publications, presentations and become competitive for investigator-initiated funding to develop program in AhR biology. This study is significant as it will determine molecular basis for the agonist specific expression and function of STC2, identify CA induced AhR dependent target genes with physiologically important roles, and will serve as a foundation for developing CA as a lead compound in the development of future cytoprotective therapeutics. To accomplish my research and career development objectives, I will receive guidance from an interdisciplinary mentoring team of extramurally funded senior investigators and technical experts. This mentorship is integrated with other enrichment events including seminars, courses, grant writing and technical workshops. The combination of mentoring and training obtained during the award period coupled with the maturation of an exciting research program namely - characterization of CA mediated AhR dependent cytoprotection in response to liver injury - will endow me with the requisite expertise to establish a career as an independent investigator.
Study identifies Stanniocalcin 2 as a central player in AhR mediated cytoprotection in response to liver injury. Mechanistic studies are designed to demonstrate that AhR activation in response to cinnabarinic acid, an endogenous AhR agonist, ameliorates chronic hepatotoxicity and identifies AhR as potential druggable target in future therapeutic strategies.
| Joshi, Aditya D; Hossain, Ekram; Elferink, Cornelis J (2017) Epigenetic Regulation by Agonist-Specific Aryl Hydrocarbon Receptor Recruitment of Metastasis-Associated Protein 2 Selectively Induces Stanniocalcin 2 Expression. Mol Pharmacol 92:366-374 |
