Úvod do molekulárnej medicíny

1. Úvoddo molekulárnej medicíny MUDr. Ing. Bc. Peter Celec, PhD.

2. Linus Carl Pauling (1901 – 1994) Nobel prize 1954 – Chemistry 1962 – Peace 2

3. „Life is a relationship between molecules, not a property of any one molecule. So is therefore disease, which endangers life. While there are molecular diseases, there are no diseased molecules.“ Linus C. Pauling, 1962 3

4. Basics 4

5. 5

6. Francis Crick 8.6.1916 – 28.7.2004

7. 7

8. James Watson 6.4.1928 –

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10. 10

11. Molecular Medicine • Based on molecular knowledge • Based on XNA • Proteomics • Genomics • Molecular interactions • Regulations • Signalling pathways • Gene therapy 11

12. What we will NOT talk about... • XNA structure • Monogenic disorders • Immunology • Carcinogenesis 12

13. Genome Genome (DNA) Transcriptome (RNA) Proteome (protein) Metabolome (pathways) 13

14. 14

15. Information processing • Communication • Intercellular • Intracellular 15

16. 16

17. Signalling pathways 17

18. Ligands • Hydrophilic • Small molecules • Larges proteins • Hydrophobic • Steroids • Thyroxine • Retinoids 18

19. Receptors • G-protein coupled • Tyrosine kinases • Ion channels • Intracellular 19

20. Signalling pathways 20

21. Phosphate 21

22. G-protein coupled 22

23. G-protein coupled • Animation 23

24. Second messangers • cAMP • cGMP • IP3 • DAG • Ca++ 24

25. Gene • „The gene is by far the most sophisticated program around.“ Bill Gates 25

26. Gene expression regulation 26

27. 27

28. Jak – Janus (Roman god of gates and doors) Kinase Jak – Just Another Kinase STAT – Signal Transducers and Activators ofTranscription APS – Adaptor protein with Pleckstrin homology and Src homology 2 domains C-Cbl - Casitas B-lineage Lymphoma EPO – Erythropoietin 28

29. Tyk2 – Tyrosine kinase 2 mTOR – mammalian Target Of Rapamycin MAPK – MAP (Microtubule Associated Protein) Kinase MAPK – MAP (Mitogen Activated Protein) Kinase ISRE – Interferon-Stimulated Response Element GAS – IFN-Gamma-Activation Site 29

30. GR – Glucocorticoid Receptor FKBP – FK506 (tacrolimus)-Binding Protein HSP – Heat Shock Protein GRE – Glucocorticoid Response Element 30

31. TGACTCA c-Fos – FBJ (Finkel MP, Biskis BO, Jinkins PB) OsteoSarcoma virus AP-1 – Activator Protein 1 31

32. FAP – c-Fos AP-1 binding site IP-1 – Inhibitory Protein 1 FAP 32

33. NFκB 33

34. FasL – Fas Ligand TRAF – TNFα Receptor Associated Factor NIK – NFκB Inducing Kinase CBP – CREB Binding Protein NFkB 34

35. MAP kinases GEF – Guanine Nucleotide Exchange Factor 35

36. MAP kinases • Animation 36

37. ...but... 37

38. Signalling pathways 38

39. Responses??? 39

40. 40

41. 41

42. Apoptosis 42

43. Apoptosis • Videos 43

44. 44

45. 45

46. Autophagy Macroautophagy Microautophagy 46

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48. 48

49. Oxygen sensing 49

50. HIF – Hypoxia Inducible Factor IGFR – Insulin like Growth Factor Receptor EGFR – Epidermal Growth Factor Receptor HER2 – Human Epidermal growth factor Receptor 2 PI3K – PhosphatidylInositol-3-Kinase AKT – serine/threonine protein kinase B FRAP – FKBP rapamycin associated protein PH – Prolin Hydroxylases HDAC – histone deacetylase VHL – von Hippel-Lindau tumour suppressor protein FIH – factor inhibiting HIF-1α B – elongin B C – elongin C C2 – cullin 2 HRE – hypoxia response element GLUT – glucose transporter ARNT – Aryl hydrocarbon Receptor Nuclear Translocator 50