Orphan nuclear receptors (those that lack a well defined physiologic ligand) control nearly every major physiologic and biochemical process in eukaryotes - cell metabolism (e.g., cholesterol, energy, bile acids), xenobiotic detoxification, cell differentiation (e.g., gastrulation, retinal development), circadian rhythm, and cancer cell growth and apoptosis (e.g., NURR77). Of these receptors, the steroid and xenobiotic receptor (SXR) is a key regulator of genes encoding drug metabolizing and transport proteins. In addition, SXR has been implicated in cancer drug resistance, carcinogenesis, innate immunity, infection control and pathophysiologic states like osteomalacia. Our laboratory focuses on defining the role of SXR and other orphans by using novel and dynamic models of human pathophysiology in (i) xenobiotic metabolism and pharmacology; (ii) carcinogenesis, organogenesis and anticancer drug resistance and (iii) innate immunity.
Recently, our laboratory has directed interests in the mammalian microbiome. We have discovered a novel link between the microbial metabolome and orphan nuclear receptor, SXR/PXR (Immunity, 2014). Further work in the laboratory is focussed on defining how the microbial environment shapes health and disease.
1. Huang H, Wang H, Ganjam K, Staudinger J, Redinbo M, Mani S. (2007) Inhibiting the transcriptional control of drug metabolism. Oncogene. 26(2):258-68.
2. Wang H, Li H, Moore LB, Maglich JM, Goodwin B, Price R, Itoop ORR, Jones SA, Wisely B, Creech K, Parks DJ, Collins JL, Willson TM, Kalpana G, Xie W, Redinbo M, Moore JT, Mani S. (2007) The Phytoestrogen Coumestrol is a Naturally Occuring Antagon ist of the Pregnane X Receptor (PXR). Mol Endocrinol. 22:838-57
3. Ekins S*, Chang C*, Mani S*, Krasowski MD, Reschly EJ, Iyer M, Kholodovych V, Ai N, Welsh WJ, Sinz M, Swaan PW, Patel R, Bachmann K.(2007) Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites. Mol Pharmacol. 72:592-603 (*equal contribution)
4. Gupta D, Venkatesh M, Wang H, Kim S, Sinz M, Goldberg GL, Whitnet K, Mani S. Expanding the roles for PXR in Cancer: Proliferation and Drug Resistance in Ovarian Cancer. (2008) Clin Cancer Res 14(17):5332-40. (F1000)
5. Das B, Madhukumar AV, Kim S, Sinz M, Zvyaga TA, Power EC, Ganellin CR, Mani S. (2008) Synthesis of novel ketoconazole derivatives as antagonists of the human Pregnane X Receptor (PXR; NR1I2l also termed SXR, PAR). Bioorg Med Chem Lett. 18(14):3974-7
6. Ekins S, Kholodovych V, Ai N, Sinz M, Gal J, Gera L, Welsh WJ, Bachmann K, Mani S. (2008) Computational discovery of novel low micromolar human pregnane x receptor antagonists. Mol Pharmacol. 74(3):662-72
7. Wallace BD, Wang H, Lane KT, Scott JE, Orans J, Koo JS, Venkatesh M, Jobin C, Yeh LA, Mani S, Redinbo MR. (2010) Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science 330(6005):831-5
8. Mani S, Boelsterli UA, Redinbo MR. (2014) Understanding and modulating mammalian-microbial communication for improved human health. Annu Rev Pharmacol Toxicol. 2014;54:559-80.
9. Biswas A, Pasquel D, Tyagi RK, Mani S. (2011)Acetylation of pregnane x receptor protein determines selective function independent of ligand activation. Biochem Biophys Res Commun. 406(3):371-6
10. Wang H, Venkatesh M, Li H, Goetz R, Mukherjee S, Biswas A, Zhu L, Kaubisch A, Wang L, Pullman J, Whitney K, Kuro-o M, Roig AI, Shay JW, Mohammadi M, Mani S. (2011) Pregnane X receptor activation induces FGF19-dependent tumor aggessiveness in humans and mice. J Clin Invest. 121(8):3220-32
9. Dou W, Mukherjee S, Li H, Venkatesh M, Wang H, Kortagere S, Peleg A, Chilimuri SS, Wang ZT, Feng Y, Fearon ER, Mani S. (2012) Alleviation of gut inflammation by Cdx2/Pxr pathway in a mouse model of chemical colitis. PLoS One 7(7):e36075
10. Li H, Redinbo MR, Venkatesh M, Ekins S, Chaudhry A, Bloch N, Negassa A, Mukherjee P, Kalpana G, Mani S. (2013) Novel yeast-based strategy unveils antagonist binding regions on the nuclear xenobiotic receptor PXR. J Biol Chem. 288(19):13655-68
11. Dou W, Zhang J, Zhang E, Sun A, Ding L, Chou G, Wang Z, Mani S. (2013) Chrysin ameliorates chemically induced colitis in the mouse through modulation of a PXR/NF-kB signaling pathway. J Pharmacol Exp Ther. 345(3):473-82
12. Venkatesh M, Mukherjee S, Wang H, Li H, Sun K, Benechet AP, Qiu Z, Maher L, Redinbo MR, Phillips RS, Fleet JC, Kortagere S, Mukherjee P, Fasano A, Le Ven J, Nicholson JK, Dumas ME, Khanna KM, and Mani S. (2014) Symbiotic Bacterial Metabolites Regulate Gastrointestinal Barrier Function via the Xenobiotic Receptor PXR and Toll-like Receptor 4. Immunity. 41(2):296-310
13. Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Bérard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L (2015). Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 350(6264):1079-84.
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