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(Usseek.com, 2016)
PRESENTED BY:
LAW CHOON YIK
SATHIAVANI
TAN KIAN LEONG
WONG CHING YEE CHRISTIN (0322752)
INTRODUCTION
Knock-in is targeted, meaning the
desired gene is inserted into a specific
locus in the target genome via
homologous recombination (Cureffi,
org, 2016)
Figure explaining the process of knock in and knock out
in mouse model (Kumar & Sahal, 2016)
A gene knock-in can be seen as a gain of
function mutation.
One example of Gene knock in mouse,
are the humanised mouse models.
Advantages of Humanized Mouse
Model
1. Mimic human pathological
conditions
2. Conduct preclinical research
3. Test compound efficacy
4. Measure compound’s effects on
human proteins (Genoway.com, 2016)
INTRODUCTION
Figure explaining differences between wild type mouse and Humanized Mouse (Genoway.com, 2016)
INTRODUCTIONALZHEIMER’S DISEASE
Alzheimer’s is a progressive disease
which cause progressive brain damage,
causing problems with memory,
thinking and behavior.
DISEASE PROGRESSION
Proteins build up in the brain to form
structures called plague and tangles.
This leads to the loss of connections
between nerve cells and eventually
causing the death of nerve cells and loss
of brain tissue
Patients will have shortage of chemical
messengers which is important for
transmitting signals around the brain.
Figure showing effects of Alzheimer’s disease to brain of patient
(Prezi.com, 2016)
APPLICATION
APPLICATION OF KNOCK IN MOUSE MODEL
It is use as models for a variety of studies which includes, human disease, target protein
expression, and cell trafficking.
GENE KNOCK IN FOR ALZHEIMERS DISEASE
Mutations in the amyloidprecursor protein gene leading to a production of excess amyloid β-peptide (αβ) is believed to be a main contributor to the dysfunction and degeneration of neurons that occurs in Alzheimer’s disease.
Figure showing the various mutation to APP gene affecting the different type of
Secretase (Bassit, Chau, Ming Li, and Tian, 2009)
APP mutations are located in exons 16
and 17, where they cluster primarily
around the secretase processing sites.
There are genes coding for β-, α-, γ-
Secretase within the APP gene.
For Example, mutations near the β-
secretase site, augment β-secretase
cleavage and increase general α β
levels, which leads to excess
production of amyloid peptide.
(Wiki.iop.kcl.ac.uk, 2016)
For study of Alzheimer’s Disease,
Mouse with overexpression of mutant
APP is generated.
APPLICATION
Figure showing the various mutation to APP gene affecting the different type of
Secretase (Bassit, Chau, Ming Li, and Tian, 2009)
Study of Alzheimer’s Disease in Mouse Model
Mouse with Swedish
Mutation
Mouse with Swedish
and Iberian Mutation
Mouse with Swedish,
Iberian and Arctic Mutation
NORMAL
α β deposition in the
cortex and
hippocampus at 6th
month
Memory impairment
at 11th Month
Accelerated α β
aggregation starting at
2nd month
Memory impairment
at 6th month.
(Mus. brc.riken.jp, 2016),
(medicalxpress.com, 2016)
APPLICATION
RESULT
Both mutation group, (Swedish And
Iberian Mutation) And ( Swedish,
Iberian, and Artic Mutation), the mice
are found to have typical α β
pathology,
Neuroinflammation, and memory
impairment (Mus. brc.riken.jp, 2016).
IMPLICATION
IMPLICATION
Various type of different mutation in the
Amyloid Precursor Protein (APP) gene can
contribute to Alzheimer’s Disease causing
its plagues and tangles formation,
degeneration of brain tissue.
The symptoms from the mouse also
matched with the symptoms from
Alzheimer’s patients.
Figure showing the effects of mutation of APP gene to mice (Mus. brc.riken.jp, 2016)
Potential Challenges in this study
1. The mouse usually over expresses the α β expression compared to a normal human which makes the Alzheimer studies hard to be compared to a human Alzheimer (Elder, Gama Sosa & De Gasperi, 2010).
2. Despite similarities between mouse and human brain, it can be challenging to draw definitive parallels between cognitive function in humans and mouse models (Oapublishinglondon.com,2016).
CHALLENGES
(Clipartpanda.com, 2016)
- Lack of progressive model
- Limited translation of preclinical findings
- Outcome measures may not be relevant to human disease
- High label-license costs
- Inability to compare results across experiments and laboratories
-Lack of standardization in outcome measures and varying methodologies (Marco
et.al, 2013).
Challenge of Knock In Mouse Model
-Mouse physiology is not the same as
humans
-Proteins expressed may not be expressed
the same as the human expression of the
same protein
Knock in gene makes mouse model too
complex.
- Which may lead to side effects and
unexplainable phenotypes
CHALLENGES
(The gramMarch Challenge, 2016)
-Knock In Mouse Model is a good strategy to
study for variety of human diseases, targeted
protein expression.
-This model have been used to study for other
diseases such as Huntington Disease and Dilated
Cardiomyopathy.
-Due to this model, scientist could deduce that
the accumulation of amyloid peptide is the
contribution to Alzheimer’s Disease.
-More effective treatment and possibly drugs can
be produced based on the studies done.
CONCLUSION
Figure depicting the disorder in movement due to
Hungtington’s Disease ( Browning and Browning, 2016)
Figure showing chest radiograph of a child with idiopathic
dilated cardiomyopathy (emedicine.medscape.com, 2016)
Bassit, B, Chau, D, Ming Li, Y and Tian, Y. (2009) An APP inhibitory domain containing the Flemish mutation residue modulates y-secretase activity for AB production. Nature Structural & Molecular Biology. [online] Available at: http://www.nature.com/nsmb/journal/v17/n2/full/nsmb.1743.html [Accessed 20 Oct. 2016].
Browning, K. and Browning, K. (2016). The disorderly dance: Huntington's Disease | Read About This. [online] Read About This. Available at: http://read-about-this.com/huntingtons-disease-the-disorderly-dance/ [Accessed 20 Oct. 2016].
Clipartpanda.com. (2016). Challenge Clipart | Clipart Panda - Free Clipart Images. [online] Available at: http://www.clipartpanda.com/categories/challenge-clipart [Accessed 20 Oct. 2016].
Cureffi.org. (2016). The difference between knock-in and transgenic mice. [online] Available at: http://www.cureffi.org/2012/11/13/the-difference-between-knock-in-and-transgenic-mice/ [Accessed 20 Oct. 2016].
Elder, G., Gama Sosa, M. and De Gasperi, R. (2010). Transgenic Mouse Models of Alzheimer's Disease. Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine, 77(1), pp.69-81.
Emedicine.medscape.com. (2016). Pediatric Dilated Cardiomyopathy: Practice Essentials, Background, Pathophysiology. [online] Available at: http://emedicine.medscape.com/article/895187-overview [Accessed 20 Oct. 2016].
Genoway.com. (2016) Humanized Mouse Model. [online] Available at: https://www.genoway.com/services/customized-mouse/knockin-models/humanisation.htm [Accessed 20 Oct. 2016].
Hall, B., Limaye, A. and Kulkarni, A. (2009). Overview: Generation of Gene Knockout Mice. Current Protocols in Cell Biology.
Kumar, V And Sahal, D. (2016). Genetic Engineering. [online] Available at: https://www.researchgate.net/figure/292262701_fig25_Figure-26-Genetic-mouse-models-A-Transgenic-mice-are-generated-by-pronuclear-injection [Accessed 20 Oct. 2016].
Marco, A, et.al. (2013) A strategy for the generation, characterization and distribution of animal models by the Michael J. Fox foundation for Parkinson’s research (2013) Special Article, 6(6), pp. 1316–1324. doi: 10.1242/dmm.011940.
Medicalxpress.com. (2016). New mouse model could revolutionize research in Alzheimer's disease. [online] Available at: http://medicalxpress.com/news/2014-04-mouse-revolutionize-alzheimer-disease.html [Accessed 20 Oct. 2016].
Mus.brc.riken.jp. (2016). September 2014 App knock-in mouse strains: new models for Alzheimer’s disease « Experimental Animal Division (RIKEN BRC). [online] Available at: http://mus.brc.riken.jp/en/mouse_of_month/sep_2014_mm [Accessed 20 Oct. 2016].
Oapublishinglondon.com. (2016). Dementia in mouse models of neurodegeneration.OA Neurosciences. [online] Available at: http://www.oapublishinglondon.com/article/1261 [Accessed 20 Oct. 2016].
prezi.com. (2016). Gene Mutation Defends Against Alzheimer's Disease. [online] Available at: https://prezi.com/tuzgjzaxcndb/gene-mutation-defends-against-alzheimers-disease/ [Accessed 19 Oct. 2016].
The gramMarch Challenge. (2016). Home. [online] Available at: http://www.grammarch.org/ [Accessed 20 Oct. 2016].
Usseek.com. (2016). mouse model images - usseek.com. [online] Available at: http://www.usseek.com/images/mouse-model [Accessed 19 Oct. 2016].
Wiki.iop.kcl.ac.uk. (2016). APP mutations. [online] Available at: http://wiki.iop.kcl.ac.uk/default.aspx/Neurodegeneration/APP%20mutations.html [Accessed 20 Oct. 2016].
REFERENCES