Pharmacogenomics and Therapeutic Target Validation of Cardiovascular - PowerPoint PPT Presentation

Pharmacogenomics and Therapeutic Target Validation of Cardiovascular Disease Models Toshio Tanaka MD, PhD Department of Molecular and Cellular Pharmacology Pharmacogenomics and Pharmacoinformatics Mie University Graduate School of Medicine February 25, 2009 UNAM, Mexico City, Mexico Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Pharmacogenomics Network Analysis of Therapeutic Genes Disease Gene Gene Gene Drug Drug Disease Therapeutic Medicine Gene Gene Gene Target Drug Therapeutic Gene Gene Gene J Pharmacol Sci 107, 8 – 14 (2008) Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Rat Cerebral Vasospasm Model HE staining (x 100) Circulation (2004)110:1839-1846 Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

HSP72 Protein after SAH Circulation (2004)110:1839-1846 Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

HSP72 Protein after SAH and Antisense Saline SAH Antisense Sense Circulation (2004)110:1839-1846 Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Effect of Antisense HSP72 ODN on Cerebral Vasospasm Circulation (2004)110:1839-1846 Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Circulation (2004)110:1839-1846 Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Effect of GGA on HSP72 Gene Expression Circulation (2004)110:1839-1846 Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Circulation (2004)110:1839-1846 Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Pharmacogenomics network analysis in treatment of cerebral vasospasm by GGA J Pharmacol Sci 107, 8 – 14 (2008) Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Heme Oxygenase - 1 mRNA in Rat Cerebral Vasospasm 20 pre-injection 16 “ 1-saline ” group “ 2-saline ” group HO-1/HO-2 “ 1-hemorrhage ” group 12 “ 2-hemorrhage ” group 8 4 0 10 min Day 12 Day 12 Day 12 10 min Day 12 10 min Day 12 10 min Day 12 10 min 10 min Basilar Occipital Frontal Parietal Brain-stem Cerebellum Artery Lobe Lobe Lobe J.Clin. Invest. 104:59-66(1999)

Effect of Antisense HO-1 ODN on Angiographic Vasospasm in Rat SAH Model % Change in Vessel Diameter 5 sen se H O-1 O DN scr as mb le d O D N 0 a nti se ns e HO -1 O D N -5 -10 -15 -20 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 J.Clin. Invest. Pre 104:59 ‐ 66(1999)

Pharmacogenomics network analysis in treatment of cerebral vasospasm by AVS(nicaraven) J Pharmacol Sci 107, 8 – 14 (2008) Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Comparative Genomics of Disease Models Human(2003) Rat/Mouse Zebrafish (2005/2002) (2009) Low Throughput High Throughput Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Advantages of Zebrafish as Disease Model Animal – 1. Short reproductive cycle. – 2. Large number of offspring per mating. – 3. Embryos are transparent allowing internal organs and neurons to be visualised. – 4. Strong correlation between human genetics, anatomy and disease. – 5. Rapid layout of body plan, allowing study of disease at early stages of embryonic development. – 6. Ethically preferred in the drive to reduce, refine and replace. – 7. Cost effective. Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Zebrafish Heart Failure Models Zebrafish Heart Failure Models Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Control Zebrafish Heart Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Zebrafish Heart Failure Model Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Carvedilol Treatment of Heart Failure Model Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Carvedilol Therapeutic Gene Discovery Carvedilol Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Laser-Captured Microdissection HF before after HF Carvedilol Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Therapeutic Gene Validation with Calvedilol Gene Expression HF Control HF Carvedilol siRNA cocktail / Morpholino Antisense 法 Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

赤： Up by PECI kd 緑： Down by PECI kd Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine

Forward Pharmacogenomics Transcriptome Genotype Phenotype Proteome Metabolome Reverse Pharmacogenomics J Pharmacol Sci 107, 8 – 14 (2008) Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics 、 Mie University Graduate School of Medicine