College aantekeningen
GKA - deeltoets 1 Gentherapie & Kanker
- Instelling
- Universiteit Utrecht (UU)
Uitgebreide samenvatting van gentherapie en kanker. Bevat alle hoorcollege aantekeningen en belangrijke informatie uit de artikelen.
[Meer zien]Voorbeeld 4 van de 75 pagina's
Voorbeeld 4 van de 75 pagina's
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Voorbeeld van de inhoud
Gentherapie 2Inleiding 2
Causes of death world wide 2
Molecular machines that control genes 3
Post transcriptional processes 6
Translatie 6
The new genetic medicines 7
Genetic therapies 11
ADA-SCID 12
Which viruses or vectors? 12
What cloning means for gene therapy 16
X-SCID 17
Gene therapy progress 23
Aplications of gene therapy 23
RNA interference 25
Gene repair (nog niet toegepast) 28
CAR-T 30
Exon skipping 30
Summary 31
Kanker 32
How cancer arises 32
Tumor suppressors 37
P53 43
Immune therapy 48
Apoptosis 54
Metastasis 59
Angiogenesis 63
From bench top to bedside 66
The hallmarks of cancer 69
Toetsvragen 75
,Gentherapie
Inleiding
Doel van de cursus
- Begrip van moleculaire achtergronden van een aantal ziekten en behandelingen
- Samenhang van oorzaken en genezing
- Wat kennis over de historie
- Gebruik van literatuur bij bestudering
- Toepassing in de vorm van een essay
Artikelen lezen is meer dan genoeg om de toetsen goed te maken. Sommige artikelen staan in de
handleiding en andere online.
Voorbeeld van een toepassing: “gekweekte huid redt leven van 7-jarige” gentherapie door
inbregen van virus met laminin gen.
Causes of death world wide
Male adult mortality risk
- In Swaziland ligt dit enorm hoog door HIV/AIDS
- In Rusland ook redelijk hoor door “mannelijk gedrag” en veel alcohol
Waarom overleiden er nog steeds zoveel mensen van kinkhoest?
Ook al zijn mensen goed gevaccineerd is het virus in het vaccin anders dan het virus dat echt
infecteert.
Hepitis B krijg je via bloed en fecal infected voedsel
,Molecular machines that control genes
Overview
- Till 1975: bacteria and promoter
- 1983: 3 classes of sequences
o Promoter
▪ RNA pol
▪ TBP = TATA-box binding protein
o Enhancer = activators
o Silencer = repressors
- 100s different proteins involed in transcription.
o Data of 2015: 1500 transcription factors in human cells, we have 20000 genes.
Summary
By 1983 investigators had established that three kinds of genetic elements, consisting of discrete
sequences of nucleotides, control the ability of RNA polymerase to initiate transcription in all
eukaryotes—from the single-celled yeast to complex multicellular organisms. One of these
elements, generally located close to the coding region, had been found to function much like a
bacterial promoter. Called a core promoter, it is the site from which the polymerase begins its
journey along the coding region. Many genes in a cell have similar core promoters.
Walter Schaffner of the University of Zurich and Steven Lanier McKnight of the Carnegie
Institution of Washington, among others, had additionally identified an unusual set of regulatory
elements called enhancers, which facilitate transcription. These sequences can be located
thousands of nucleotides up-stream or downstream from the core promoter—that is, incredibly
far from it. And subsequent studies had uncovered the existence of silencers, which help to
inhibit transcription and, again, can be located a long distance from the core promoter.
It was evident that enhancers and silencers could not control the activity of RNA polymerase by
themselves. Presumably they served as docking sites for a large family of proteins. The proteins
that bound to enhancers and silencers—now called activators and repressors—then carried
stimulatory or repressive messages directly or indirectly to RNA polymerase.
In 1982 William S. Dynan, a postdoctoral fellow in my laboratory, determined that some protein
in a mixture of nuclear proteins fit all the requirements of a transcription factor. It bound to a
regulatory element common to a select set of genes—an enhancer sequence known as the GC
box (because of its abundance of G and C nucleotides). More important, when added to a
preparation of nuclear proteins that included RNA polymerase, the substance markedly increased
the transcription only of genes carrying the GC box. Thus, we had identified the first human
transcription factor able to recognize a specific regulatory sequence. We called it specificity
protein 1 (Sp1).
We immediately set out to purify the molecule. One daunting aspect of this work was the fact
that transcription factors tend to appear only in minuscule quantities in cells. Typically, less than
a thousandth of a percent of the total protein content of a human cell consists of any particular
factor.
, Because Sp1 selectively recognized the GC box, Kadonaga synthesized DNA molecules
composed entirely of that box and chemically anchored them to solid beads. Then he passed a
complex mixture of human nuclear proteins over the DNA, predicting that only Sp1 would stick
to it.
One end of the molecule contained a region that obviously folded up into three “zinc fingers.”
Zinc-finger structures (een zinc gebonden door 4 aminozuren, cystine en histidine), in which
parts of a protein fold around a zinc atom, are now known to act as the “hooks”
that attach many activator proteins to DNA.
The other end of Sp1 contained a domain consisting of two discrete segments
filled with a preponderance of the amino acid glutamine (Q). We strongly
suspected that this region played an important role during transcription be-
cause of a striking finding. In test-tube experiments, mutant Sp1 molecules
lacking the domain could bind to DNA perfectly well, but they failed to
stimulate gene transcription. This outcome indicated that Sp1 did not affect
transcription solely by combining with DNA; it worked by using its glutamine-
rich segment—now known as an activation domain—to interact with some
other part of the transcription machinery (co-activator).
In the mid-1980s Robert G. Roeder and his colleagues at the Rockefeller
University had shown that RNA polymerase cannot transcribe eukaryotic genes unless several
other transcription factors—now called basal factors—also collect on the core promoter. And
over the course of the 1980s, Roeder’s laboratory and others had identified at least six of those
essential factors, called A, B, D, E, F and H.
By the late 1980s it was apparent that human cells harbor at least two separate classes of
transcription factors. Basal factors are required for initiation of transcription in all genes; other
proteins—activators and repressors—dictate the rate at which the basal complex initiates
transcription.
These various discoveries suggested that the glutamine-rich domain of Sp1 enhanced
transcription by contacting a basal factor. More specifically, we suspected that Sp1 latched on to
factor D, and facilitated its attachment to the promoter. We focused on this subunit because
Phillip A. Sharp and Stephen Buratowski of the Massachusetts Institute of Technology had
shown that it can land on the core promoter before all other basal factors and can facilitate
assembly of the complete basal engine. In fact, factor D is the only basal component able to
recognize DNA. It binds selectively to a sequence called the TATA box, found in the core
promoters of many eukaryotic genes.
The protein, named TBP (for TATA binding protein, buigt het DNA zodat de promotor
beschikbaar wordt), recognized and bound selectively to the TATA box and led to a low level of
transcription when it was joined at the core promoter by RNA polymerase and other constituents
of the basal machinery.
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