Molekulárna biológia v medicíne - uniba.sk · 4 •„Life is a relationship between molecules,...
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Transcript of Molekulárna biológia v medicíne - uniba.sk · 4 •„Life is a relationship between molecules,...
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
Francis Crick
(1916 – 2004)
Nobel prize
1962 – Physiology or medicine
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James Dewey Watson
(1928 – )
Nobel prize
1962 – Physiology or medicine
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1848
Ľudovít Štúr Johann Gregor Mendel
• Pathological anatomy
• Cell theory– Omnis cellula e cellula
Rudolf Virchow
• Biochemistry
• Proteins• Hemoglobin
Felix Hoppe-Seyler
Friedrich Miescher
Friedrich Miescher
• Pus from bandage
• Nuclein• Important for inheritance
Albrecht Kossel
• Theophylline
• Nobel prize 1910• Composition of nucleic acids• Adenine, guanine, cytosine, thymine
caffeine
sugar
bases
phosphate
Erwin Chargaff
Bases
Frederick Griffith
• In vivo experiments
• Pathogenic bacteria
• DNA and inheritance• Transforming factor
Osvald Avery
Frederick Sanger
(1918 – 2013)
Nobel prize
1958 – Chemistry
1980 – Chemistry
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Kary Banks Mullis
(1944 – )
Nobel prize
1993 – Chemistry
John Craig Venter(1946 - )
Francis Sellers Collins(1950 - )
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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
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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. 1941b. 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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Causes of death
• Ľudovít Štúr
• Johann Gregor Mendel
• Friedrich Miescher
• Rudolf Virchow
• Albrecht Kossel
• Oswald Avery
• Erwin Chargaff
• Francis Crick
• sepsis (40y)
• nephritis (61y)
• tuberculosis (51y)
• trombosis (80y)
• infarction (73y)
• cancer (77y)
• heart failure (96y)
• cancer (88y)
Pathophysiology
Disease
Interactions
Environment
Genes
Heritability
large
Disease
Interactions
Environment
Genes
small
Disease
Interactions
EnvironmentGenes
NGS
Indivdualized medicine
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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 genome
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Synthetic biology
Gene therapy
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Gene therapy
Shinya Yamanaka
(1962 – )
Nobelova cena
2012 – Fyziológia alebo medicína
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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Individualized medicine
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Personalized medicine
23andme
23andme
Better not to know?
Preventive medicine
Physicians are afraid of wrong interpretations
Cholesterol? Blood pressure?
Fear comes from the unknown
