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Nuclear Receptors, in Vitro and in Vivo Approaches

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Nuclear Receptors, in Vitro and in Vivo Approaches Nuclear receptors: in vitro and in vivo approaches Parma, June 13-15 2017 Adriana Maggi University of Milan www.cend.unimi.it Intracellular Receptors, Androgen Receptor (AR; NR3C4) Aryl Hydrocarbon Receptor (AhR) a family of 48 members Constitutive Androstane Receptor (CAR; NR1I3) in humans Estrogen Receptor Alpha (ERα; NR3A1) Estrogen Receptor Beta (ERβ; NR3A2) Estrogen Related Receptor Alpha (ERRα; Pregnane X Receptor (PXR; NR1I2) NR3B1) Progesterone Receptor (PGR; NR3C3) Estrogen Related Receptor Gamma (ERRɣ; Retinoic Acid Receptor Alpha (RARα; NR1B1) NR3B3) Retinoic Acid Receptor Beta (RARβ; NR1B2) Farnesoid X Receptor (FXR; NR1H4) Retinoic Acid Receptor Gamma (RARɣ; NR1B3) Glucocorticoid Receptor (GR; NR3C1) RAR-related Orphan Receptor Alpha (RORα; Liver Receptor Homolog-1 (LRH-1; NR5A2) NR1F1) Liver X Receptor Alpha (LXRα; NR1H3) RAR-related Orphan Receptor Gamma (RORɣ; Liver X Receptor Beta (LXRβ; NR1H2) NR1F3) Mineralocorticoid Receptor (MR; NR3C2) Retinoid X Receptor Alpha (RXRα; NR2B1) Peroxisome Proliferator-Activated Receptor Retinoid X Receptor Beta (RXRb; NR2B2) Alpha (PPARα; NR1C1) Retinoid X Receptor Gamma (RXRɣ; NR2B3) Peroxisome Proliferator-Activated Receptor Thyroid Hormone Receptor Alpha (TRα; Delta (PPARδ; NR1C2) NR1A1) Peroxisome Proliferator-Activated Receptor Thyroid Hormone Receptor Beta (TRβ; NR1A2) Gamma (PPARɣ; NR1C3) Vitamin D Receptor (VDR; NR1I1) NR Functional Classification The endogenous ligands for Intracellular Receptors MECHANISM OF ACTION 1. MECHANISM OF ACTION 2. THE PHARMACOLOGY OF INTRACELLULAR RECEPTORS THE PHARMACOLOGY OF INTRACELLULAR RECEPTORS 2. THE COMPLEXITY OF ESTROGEN ACTION ERalpha ERbeta IP3k cAMP SP1 NFKB AP1 THE TOOLS TO STUDY INTRACELLULAR RECEPTOR ACTIVITIES INTRACELLULAR RECEPTORS : THE TOOLS INTRACELLULAR RECEPTORS : THE TOOLS FUNCTIONAL CHARACTERIZATION OF ER LIGANDS BINDING ASSAY FUNCTIONAL CHARACTERIZATION OF ER LIGANDS ER cDNA ERE LUC TRANSFECTION ASSAY ER ER Units LUC LUC LUC CTR E2 CTR FUNCTIONAL CHARACTERIZATION OF ER LIGANDS TRANSFECTION ASSAY LigandsLigand NR NR NR NR Reporter green fluorescent dye 4 ACTIVATION OF ERE-LUC REPORTER IN MOUSE HEPATOCYTES 15 minutes 2 hours 18 hours 1 week 2500 2400 + *** 2400 EC =4.89nM Vehicle EC =4.89nM 50 2000 50 ** 1600 1500 1600 E2 1 nM g Protein g g Protein g 1000 *** g Protein g ** E 5 nM 800 2 500 800 RLU/ RLU/ Photon Emission Photon E 10 nM 0 RLU/ 2 vehicle 0.01 0.05 0.1 0.5 1 5 10 0.01 0.1 1 10 0.01 0.1 1 10 - E [ ]nM E2 [ ]nM 2 E2 [ ]nM 800 800 600 600 400 400 g Protein g g Protein g 200 200 RLU/ RLU/ 0 0 M M M M M M M M M 2 2 WME Vehicle EAA+E Valine EAA 1 E+NE 1 NEAA+E LeucineLysine EAA 100 EAA500 NEAA 1 Arginine Histidine NEAA 100NEAA500 E+NE 100E+NE 500 ThreonineTryptophanMethionine Isoleucine Phenylalanine FUNCTIONAL CHARACTERIZATION OF ER LIGANDS REPORTER MICE, THE ULTIMATE FUNCTIONAL ASSAY LigandsLigand NR NR NR NR Reporter green fluorescent dye 4 ERE-Luc reporter mice to study the dynamics of ER activity in living mice estrogen +/- +/- INSULATOR INSULATOR ERE 2x TK ( MAR ) firefly luciferase ( MAR ) luciferin + ATP = oxyluciferin + AMP + light Ciana et al., Mol. Endocrinol. 2001 Ciana et al., Nature Med. 2003 SEMI-QUANTITATIVE ANALYSIS OF ER ACTIVITY I N THE ERE-LUC REPORTER MOUSE 2000 * TIME 0 emission 3 HOURS 1000 * 6 HOURS photon TIME 0 3 HOURS 6 HOURS 24 HOURS 24 HOURS Liver Access to the dynamic of molecular events in complex organisms Access to the dynamic of drug effects 3Rs rule in drug development THE ERE-Luc REPORTER MOUSE A PHARMACOLOGICAL APPLICATION pellet days of treatment CONTROLS In vivo analysis of photon emission Manual Automatic REFERENCE DRUG DRUG OF INTEREST Rando et al. 2009 HEPATIC AREA ABDOMEN hepatic abdomen ACUTE 2000 250 1500 1000 200 500 400 150 300 100 s (vs cyc=100%) s (vs cyc=100%) 200 2 2 50 100 cts/cm cts/cm 0 hepatic 0 abdomen 3500 250 E2 E2 ovx cyc ovx cyc OSP BZA LAS OSP LAS BZA 2500 RAL2 PCUD RAL2 PCUD RAL10 P+BZA P+BZA RAL10 CHRONIC 1500 200 500 150 300 AUC AUC 200 100 100 50 0 0 E2 E2 ovx cyc BZA LAS ovx cyc BZA OSP LAS OSP RAL2 TAM TAM RAL2 PCUD RAL10P+BZA PCUDP+BZARAL10 ovx cyc E2 CE CE+BZA BZA RAL2 RAL10 LAS OSP TAM Della Torre et al. Endocrinol 2011 SERCHING FOR NOVEL MODALITIES TO MEASURE THE EFFICACY OF SERMs N° peaks, amplitude, frequency CHEST 400000 300000 /sr 2 200000 p/s/cm 100000 Photon emission Photon AUC 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Days GENITAL AREA SKELETAL AREA 8 8 6 6 * * * ** A 4 4 2 2 Peaks/21d 0 0 12 12 9 * * 9 6 * 6 B * 3 3 Amplitude 0 0 6 6 * 5 5 C 4 4 3 3 Period (d) Period 2 2 800 250 600 200 * 400 * 300 * 150 * * D AUC 200 * 100 100 50 0 0 600 200 450 * 150 * 300 * 200 E 100 * ovx cyc E2 CE 150CE+BZA*BZA RAL2 RAL10 LAS OSP TAM Potency 50 100 * 50 0 0 Rando et al, Mol. Endocrinol. 2010 PHENETICS OF DRUG ACTION THE APPLICATION OF AGGLOMERATIVE HIERARCHICAL CLUSTERING TO THE STUDY OF THE IN VIVO ACTION OF ESTROGENIC COMPOUNDS clustering data Space-temporal analysis of drug action in to generate novelliving families animals of compounds Genital area Skeletal area ovx cyc E2 CE CE+BZA BZA RAL2 RAL10 LAS OSP TAM Rando et al, Mol. Endocrinol. 2010 A Genital area C Reverse Medicinal Chemistry B Skeletal area Cl ovx cyc E2 CE CE+BZA BZA RAL2 RAL10 LAS OSP TAM Rando et al, Mol. Endocrinol. 2010 Time and space: the dimensions for a full understanding of the effect of drugs and pollutants ability to interfere with intracellular receptors activities CONCLUSION 2 The ERE-Luc reporter mouse represents a novel tool to identify synthetic compounds and ED present in the environment or in the alimentary chain and to provide a comprehensive view on their activity on Ers whole body University of Milan Center of Excellence on Neurodegenerative Diseaseas Past Collaborators : Collaborators: Roberta Fontana Elisabetta Vegeto Luisa Ottobrini Paolo Ciana Gianpaolo Rando Gianpaolo Rando Valeria Benedusi Paolo Ciana Sara Della Torre Funding: Saba Khalilpour Federica Lolli Nicoletta Rizzi Alessandro Villa Clara Meda Sara Della Torre Monica Rebecchi Clara Meda “The whole is more than the sum of its parts “ Aristotle (384 BC – 322 BC) Methapysics Intracellular Receptors, are transcription factors able to bind the DNA .
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