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Úvod
do molekulárnej medicíny
Doc. MUDr. Ing. RNDr. Peter Celec, DrSc., MPH
www.imbm.sk
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Linus Carl Pauling
(1901 – 1994)
Nobel prize
1954 – Chemistry
1962 – Peace
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„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
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Francis Crick
(1916 – 2004)
Nobel prize
1962 – Physiology or medicine
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James Watson
(1928 – )
Nobel prize
1962 – Physiology or medicine
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Genome (DNA)
Transcriptome (RNA)
Proteome (protein)
Metabolome (pathways)
Systems biology
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DNA is information!!!
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Information processing
Communication
Intercellular
Intracellular
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Signalling pathways
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Reception
Ligands
Hydrophilic
Small molecules
Larges proteins
Hydrophobic
Steroids
Thyroxine
Retinoids
Receptors
G-protein coupled
Tyrosine kinases
Ion channels
Intracellular
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Signalling pathways
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G-protein coupled
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Phosphate
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MAP kinases
GEF – Guanine Nucleotide Exchange Factor
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Second messangers
cAMP
cGMP
IP3
DAG
Ca++
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Gene
„The gene is by far the most sophisticated
program around.“
Bill Gates
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Nobel Prize in Chemistry 2006
Roger D. Kornberg
USA
Stanford University
b. 1947
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"for his studies of the molecular basis of
eukaryotic transcription"
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Gene expression regulation
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Jak – Janus (Roman god of gates and doors) Kinase
Jak – Just Another Kinase
STAT – Signal Transducers and Activators of Transcription
APS – Adaptor protein with Pleckstrin homology and Src homology 2 domains
C-Cbl - Casitas B-lineage Lymphoma
EPO – Erythropoietin
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GR – Glucocorticoid Receptor
FKBP – FK506 (tacrolimus)-Binding Protein
HSP – Heat Shock Protein
GRE – Glucocorticoid Response Element
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TGACTCA
c-Fos – FBJ (Finkel MP, Biskis BO, Jinkins PB) OsteoSarcoma virus
AP-1 – Activator Protein 1
AP-1
FAP
FAP – c-Fos AP-1 binding site
IP-1 – Inhibitory Protein 1
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NFκB
FasL – Fas Ligand
TRAF – TNFα Receptor Associated Factor
NIK – NFκB Inducing Kinase
CBP – CREB Binding Protein
NFkB
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...but...
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Signalling pathways
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Responses???
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Cell death
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Apoptosis
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Autophagy
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Autophagy
Microautophagy
Macroautophagy
Chaperone-mediated
Pexophagy
Mitophagy
Xenophagy
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Oxygen sensingHIF – 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
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Oxygen sensingHIF – 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
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Angiogenesis
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Napoleone Ferrara
Genentech
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Aaron
Ciechanover
Avram
Hershko
Irwin
Rose
1/3 of the prize
Israel
1/3 of the prize
Israel
1/3 of the prize
USA
Technion – Israel
Instutute of
Technology
Haifa, Israel
Technion – Israel
Institute of
Technology
Haifa, Israel
University of California
Irvine, CA, USA
b. 1947 b. 1937
(Karcag, Hungary)
b. 1926
The Nobel Prize in Chemistry 2004"for the discovery of ubiquitin-mediated
protein degradation"
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Ub
E1
Ub
E2
Ub
E3
Ub
26S proteasome degradation
Target
UbUbUb
Ubiquitin pathway
Ubi-activating E Ubi-conjugating E Ubi-ligase
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Ub
ATP AMP + PPi
E1E1C
E2C
E2
E3C
E3
Protein K
Protein
E3
E3
Protein K
Protein K
E2
E3Protein K
E3
E2C
Ub
Protein
AMP + PPi
Protein K
Proteosynthesis
Antigen presentation
H
A
B
C1
C2
D
E
Ub
Protein
ATP
Protein
Protein
I
F
G
J
Nobel Prize in Physiology or Medicine 2007
47
Mario R. Capecchi Sir Martin J. Evans Oliver Smithies
1/3 of the prize 1/3 of the prize 1/3 of the prize
USA United Kingdom USA
University of Utah
Salt Lake City, UT,
USA; Howard
Hughes Medical
Institute
Cardiff University
Cardiff, United
Kingdom
University of North
Carolina at Chapel
Hill
Chapel Hill, NC,
USA
b. 1937
(in Italy)b. 1941
b. 1925
(in United Kingdom)
"for their discoveries of
principles for introducing
specific gene modifications
in mice by the use of
embryonic stem cells"
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Individualized medicine
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Dennis Lo
Fetus is similar to a tumor
Non-invasive prenatal diagnosis
Sex
RhD
Aneuploidies
Fetal genome52
Synthetic biology
Production of synthetic microorganisms
Technology (detoxification, production,
therapy?)
Genome editing
Feng Zhang
Clustered Regularly Interspaced Short
Palindromic Repeats (CRISPR)
CRISPR associated (Cas) nuclease, Cas9
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Shinya Yamanaka(1962 - )
iPSC
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Shinya Yamanaka
Kyoto University
iPS
Reprogramming of differentiated
cells
Pluripotency
No immune response
Without retroviral vectors
Without oncogenes
Parabiosis
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Prevention of wrong advices
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