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http://www.youtube.com/user/BritishHeartFound#p/u/0/djFb8PGS34g
Compare and contrast the Drosophila and Zebrafish as animal systems for the study
of human disease.
April, Laura, Alaa
What’s an Animal System?
An animal system is a living, non-human animal used for the research and investigation of
human disease
Drosophila Melangaster
Drosophila MelangasterDrosophila Melangaster
Fruit fly
One of the first to be used
Similarities to human genes
Used for high throughput drug screening
Advantages
Fast development
Carry out sophisticated loss-of-function and gain-of-function genetic analysis
Easy and rapid genetic analysis
Short generation time
High fecundity
Easy maintenance in large numbers
Mutants are easier to obtain
Neurodegenerative Diseases
Generation of transgenic Drosophila which over express mutated proteins causing them to develop degenerative diseases allowing us to use them as models for Alzeimers and Huntingtons disease.
Animal models have helped us find possible cause of HD: (1) Expansion of unstable CAG repeat (2) Effect of Quasi-pure polyglutamine tracts (3) Implications to Caspases 1 & 3
Parkinson’s disease
Disease background:-Progressive degenerate disorder of the CNS-Idopathic disorder-Symptoms are movement related-Dominant cause = mutations of alpha synuclein
Animal model:-Flies with mutant alpha synuclein have developed motor impairment-Research on Parkin specific mutations in association with indirect fly muscles
Spinal Muscular Atrophy (SMA)
Disease background:-Characterised by degeneration of motor neurons-Mutation of Survival Motor Neuron(SMN) gene in humans
Model:-Model mimics phenotype of human disorder-The Fibroblast Growth Factor (FGF) signalling pathway in humans is the homolog to the drosophilas’ SMN -SMN gene mutation results in:1)Reduced viability 2)Decreased motility 3)Develops muscular atrophy in the adult thorax
Heart DiseaseDisease background -Umbrella term for many heart related diseases-Leading Cause of death in the UK -Examples: CHD, Cardiovascular disease and Heart failure.
Animal Model-New research field -Less complicated circulatory system than in humans-From screening 7,061, 500 were found to be associated with cardiovascular disorders
-Mutant flies have low levels of PE-Initiate a new mechanism for synthesising fats-This is the protein SREBP which activates enzymes that synthesise fats-High levels of this protein along with triglycerides and heart damaging fats.-Fat accumulation and distribution to the membrane leads to heart problems.-Inhibiting this protein allows restoration of fat balances and therefore reduced heart malfunctions.
ZebrafishZebrafish
Zebrafish
Danio rerio
Tropical freshwater fish
Genetically and morphologically similar to humans
Good human disease models
Advantages
Short generation time (especially for a vertebrate)
Transparent embryo
Genetic tractability
Easy manipulation
Spinal Muscular Atrophy(SMA)
The Morpholino Spinal Motor Neuron(SMN) protein gene is the faulty gene is some forms of SMA
This has been researched using gene knockdowns of the SMN gene in Zebrafish embryos
Morphant axons exhibit motor axon specific pathofinding defects with no increase in the rate of apoptosis in motor neurons.
Concluding - SMN has an important function in motor axon development and maintenance
Heart Disease
Special ability to regenerate damaged heart
Our capability of developing our heart once should mean we can do it again?
Fast heart development - 12 hours
Transparent embryo allows viewing of heart and blood vessel development
Similarities in key genes and chemical messengers means we can try to replicate the process in humans
Drosophila Vs.
Zebrafish
Compare
Both have high Fecundity
Both used for drug discovery
Both develop rapidly - Allowing rapid genetic analysis
Embryos develop outside and not in the mother therefore developmental stages can be monitored
Easy access with fewer ethical objections
ContrastInvertebrate
7-19 generation time
Micromanipulation is limited
Non-transparent embryo
DNA content - 180 million
58% genetic similarity to humans
Vertebrate
3-4 months generation time
Micromanipulation is greater
Transparent embryos
DNA content - 1900 million
82% genetic similaritiey to humans
Drosophila Zebrafish
Conclusion - why we think Zebrafish are better models.
Zebrafish is a more reliable study for heart disease
They are vertebrates
Greater genetic similarities
Similar organ systems
Similar developmental pathways
Females are easier to work with as they are larger
References Peter.J.Russel. Essential I-Genetics (first edition)Pearson education
Griffths, Miller, Suzuki, Lewontin & GelbartAn introduction to genetic analysis (7th edition)W.H.Freeman
http://www.bhf.org.uk/British heart foundation
Modeling spinal muscular atrophy in Drosophila links Smn to FGF signalingAnindya Sen1, Takakazu Yokokura1, Mark W. Kankel1, Douglas N. Dimlich1, Jan Manent1, Subhabrata Sanyal2, and Spyros Artavanis-Tsakonas1,3
Richard Butler In vivo analysis of neurological disease mechanisms in zebrafish.Thesis 15014
http://www.nature.com/ng/journal/v39/n5/full/ng0507-589.html
http://www.ncbi.nlm.nih.gov/pubmed/11206415
http://pubs.acs.org/subscribe/journals/mdd/v07/i06/html/604feature_ma.html
http://genome.cshlp.org/content/9/2/99.long
http://www.statistics.gov.uk/articles/hsq/hsq28_death.pdf
http://www.shef.ac.uk/mediacentre/index.html
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