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Thalassemia Research Center Mahidol University Suthat Fucharoen M.D. Thalassemia Research Center

Thalassemia Research Center Mahidol University Suthat Fucharoen M.D. Thalassemia Research Center Inst. Of Science and Technology for Research and Development Email: grsfc@mahidol.ac.th. Outline presentation What is thalassemia Summary of research outcome Research network

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Thalassemia Research Center Mahidol University Suthat Fucharoen M.D. Thalassemia Research Center

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  1. Thalassemia Research Center Mahidol University Suthat Fucharoen M.D. Thalassemia Research Center Inst. Of Science and Technology for Research and Development Email: grsfc@mahidol.ac.th

  2. Outline presentation What is thalassemia Summary of research outcome Research network Future research work

  3. Thalassemia in Thailand Total number of thalassemic patients and the number of births per year (total births = 800,000/year) Fucharoen S. and Winichagoon P., 1988

  4. Pathophysiology of –Thalassemia/Hb E Disease

  5. TREATMENT OF THALASSEMIA 1. CONVENTIONAL TREATMENT - BLOOD TRANSFUSION - IRON CHELATION 2. HEMOGLOBIN F STIMULATION 3. TREATMENT OF COMPLICATION - INFECTIONS - HEART FAILURE ETC. 4. CURE - BONE MARROW AND STEM CELLS TRANSPLANTATION - ? GENE THERAPY

  6. Outline presentation What is thalassemia Summary of research outcome Research network Future research work

  7. Thalassemia Research at Mahidol University Epidemiologic study Molecular biology Pathophysiologic changes Laboratory diagnosis Iron overload, iron metabolism and iron chelation Therapeutic intervention eg. Hb F enhancers Prevention and control of thalassemia Genotype-phenotype interaction Thalassemic and transgenic mice model

  8. Inappropriate suppression of hepcidin by erythroblast-secreted factors. GDF15 overexpression contributes to iron overload in b-thalassemia by inhibiting hepcidin expression Transforming growth factor-beta superfamily member, growth differentiation factor 15 (GDF15) Tanno et.al. 2007

  9. DESFERRIOXAMINE

  10. Preliminary data on serum ferritin in ADULT and pediatric patients after 6mths of GPO-L-ONE-2 Pediatrics Adults Average dose in ped. = 75-80 MKD Average dose in adult = 50-55 MKD

  11. Case Registration (year) CMU MOPH 40 35 35 31 30 Hb E/beta-thal 26 25 25 beta-Thal major 24 24 22 22 Number 21 20 15 15 11 11 10 10 9 9 5 5 4 3 3 0 0 93 94 95 96 97 98 99 00 01 02 Year

  12. Immunochromatographic Strip Test for -Thalassemia 0.1 ml. blood + hemolysis agent 2. Insert strip, leave 2 min. 4. Read result 3. wash 3 minutes

  13. Variable Severity in -Thalassemia Disorder

  14. CANDIDATE GENES Apoptosis Interesting Function Proteolysis Apoptosis/Cell Cycle Regulation Fas apoptotic inhibitory molecule 3 NIMA (never in mitosis gene a)- related kinase 11 sestrin 2 NACHT, leucine rich repeat and PYD containing 14  leukemia inhibitory factor receptor phosphoinositide-3-kinase, class 2, alpha polypeptide polymerase (RNA) III (DNA directed) polypeptide D, 44kDa  DnaJ (Hsp40) related, subfamily B, member 13 axin Wilms tumor associated protein interleukin 24 Protease and Ubiquitination calpain 1, (mu/I) large subunit  NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 5, 16kDa HtrA serine peptidase 1 ADAM metallopeptidase with thrombospondin type 1 motif, 6 neurolysin (metallopeptidase M3 family) serpin peptidase inhibitor, clade B, member 11 carboxypeptidase E ring finger protein 152 F-box and WD-40 domain protein 11 N-acetylated alpha-linked acidic dipeptidase-like 1 Regulatory Elements high-mobility group box 1 T-box 2  integrin beta 4 binding protein  ets variant gene 6 (TEL oncogene) AT rich interactive domain 5B (MRF1-like) recombining binding protein suppressor of hairless (Drosophila) eukaryotic translation initiation factor 2C, 4 endothelin converting enzyme 1 SRY (sex determining region Y)-box 5 pre-B-cell leukemia transcription factor 3 transcription factor activity-1 SET domain and mariner transposase fusion gene sex comb on midleg homolog 1 (Drosophila) eukaryotic translation initiation factor 2C, 3 transcription factor activity-2 zinc finger protein 659  zinc finger protein 214  zinc finger protein 682  zinc finger protein 91 zinc finger protein 403 zinc finger protein 192 zinc finger protein 609 Regulatory Elements SIGNAL TRANSDUCTION mitogen-activated protein kinase kinase kinase 9 v-ros UR2 sarcoma virus oncogene homolog 1 (avian) protein-coupled receptor 22 adenylate kinase 5 FERM, RhoGEF and pleckstrin domain protein protein tyrosine kinase 2 beta TAO kinase 3 receptor tyrosine kinase-like orphan receptor membrane associated guanylate kinase, WW and PDZ domain containing protein kinase, cGMP-dependent, type I src family associated phosphoprotein 1 Rho guanine nucleotide exchange factor (GEF) 12 HSA275986 transcription factor SMIF vascular cell adhesion molecule 1 regulator of G-protein signalling like 2 tumor necrosis factor receptor superfamily, member 11, activator of NFKB INTERESTING BIOLOGICAL FUNCTION chromatin assembly factor 1, subunit A (p150) oncoprotein induced transcript 3 hemochromatosis type 2 (juvenile) frataxin gastric inhibitory polypeptide  glucosidase, beta, acid 3 (cytosolic) glutathione S-transferase M5 lipase glucose transporter ATPase, Ca++ transporting ATPase, H+ transporting potassium voltage-gated channel calcium channel, voltage-dependent chloride intracellular channel 5 cell adhesion Golgi function mitochondrial protein Non-associated Function Unknown Function Hypothetical Protein

  15. Results of 2nd genome-wide association

  16. E Whole locus of human βE-globin transgene 2. 3.

  17. Rescue RBC morphology Wild type HbE transgenic 0-heterozygote Double heterozygote

  18. Comparison of Publication from Five ASIAN Countries in the Field of Thalassemia, 1998-2008 This information is taken from PubMed.

  19. Number of Students Graduated

  20. Outline presentation What is thalassemia Summary of research outcome Research network Future research work

  21. Molecular Biology (Pranee Winichgoon & Saovaros Svasti, Molecular Biologist) Protein structure & Function (Jisnusan Svasti, Biochemist) Globin Gene Mutation Disease ModifierGenes (Saovaros Svasti , Molecular Biologist / Chayanon Peerapittayamongkol, Biochemist / Vip Viprakasit, Hematologist) Malaria & Red Cell (Prapon Wilairat, Biochemist Red Cell Biology(Kovit Pattanapunyasat, Hematologist) Abnormal Hbs Genotype-Phenotype Red Cell Iron Overload & Chelators Thrombosis Iron Metabolism (Pensri Pootrakul, Hematologist) Iron Chelator (Prapin Wilairat, Physical Chemist & Somdet Srichairatanakool, Hematologist) Oxidative Stress Coagulation Study (Phantip Vattanaviboon, Hematologist / Punnee Butthep, Pathologist) Free Radicals (Udom Chantaraksri & Noppawan Phumala Morales, Pharmacologist/ Ruchaneekorn Kalpravidh, Biochemist) • THALASSEMIA • Genetic - Cardiology • Hematology - Infections • Pulmonary - Pathology • ect.

  22. Sweden: Bengt Fadeel NIH: Jeffry L. Miller & Griffin P. Rodgers Germany: Helmut Bartsch RIKEN: Yusuke Nakamura UK: David Weatherall & Robert Hider Kyushu: Tsukuru Umemura UNC: Ryszard Kole France: METI/CEA Singapore: Tang Kai Australia: Jim Vadolas

  23. (+) (+) (+) (+)

  24. Asian Network Thalassemia 1. Australia (John Prior) 2. Bangladesh (Syed Khairul Amin) 3. Cambodia (Sam Vuthy, Robyn Devenish) 4. China, Guangxi (Chen Ping) 5. China, Hong Kong (Vivian Chan) 6. India (Roshan Colah) 7. Indonesia (Iswari Setianingsih) 8. Laos (Douangdao Souk Aloun) 9. Malaysia (Elizabeth George) 10. Maldives (Naila Firdous) 11. Myanmar (Sann Sanda Khin) 12. Singapore (Hai Yang Law) 13. Sri Lanka (Shanthimala de Silva) 14. Taiwan (Ching-Tien Peng) 15. Thailand (Vichai Tienthavorn) 16. Vietnam (Lam Thi My) Prawase Wasi Mahidol University Sir David Weatherall Oxford University Alan Bittles Edith Cowan University

  25. Asian Network Thalassemia Control Bangkok, July 2005

  26. Outline presentation What is thalassemia Summary of research outcome Research network Future research work

  27. Future Research Work • Basic research • Role of miRNA and ncRNA in the • regulation of globin genes expression • erythropoiesis and apoptosis • Pathophysiology • Cardiac complications • Iron overload, iron metabolism, Iron absorption

  28. Future Research Work • 3. Genotype-phenotype • Identify disease modifier genes from SNPs analysis and their functions • 4. Proteomic study in thalassemic plasma • 5. Intervention • Antioxidants • siRNA • ASO and gene therapy • Hb F enhancer • Iron chelators • 6. Prevention and control of thalassemia in Asia

  29. CONTINUITY 1950 1960 1970

  30. Team Work January 2003

  31. Team Work April 2003

  32. Problems: • Man power • Graduate Program

  33. Thank you

  34. Funding Annual Budget 493,100 Baht Research Grant 10,865,000Baht Granting Agencies: TRF, NRCT,NSTDA/BIOTEC, NIH

  35. Gene Therapy for Thalassemia Conversion to transfusion independence (I) Last RBC transfusion 11.5 months ago Months post-transplantation

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