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Summary BMS41 Advanced Models of human disease
Notes from all the lectures
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Advanced models of human diseaseLecture 1
Animal model: living organism with an inherited, naturally acquired or induced
pathological process that in one or more respects closely resembles the same
phenomenon in man.
Why do we use animal models?
1. To gain insights into the pathogenesis of the disease phenotype. They help us
determine which gene is causing the disease and the mechanism of the disease.
2. To identify therapeutic targets and diagnostic markers. A commonly used model is
the kidney disease animal models.
Metabolomics has been widely used for identifying metabolites in CKD and
its complication in serum, plasma, urine and tissues from both animal
models and CKD patients.
Example: salt reabsorption in hypertensive patients
3. To test potential treatments. Drug discovery preclinical clinical trials (phase
1, 2 and 3) FDA review LG-scale MFG post-marketing surveillance.
When do we consider the use of animal models? when in vitro and/or computational
models cannot reproduce the level of biological complexity required to solve our scientific
question. Animal models cannot be used if the in vitro model is valid enough for the study.
Diseases with multiple manifestations in different organs are targets for animal models.
However, it is best to combine in vitro and in vivo models.
Organoid models: Advanced models respect to in vitro and/or
computational models for the study of human disease
Animal models: More in vivo whole body physiology
How to choose your model?
- Appropriateness as an analog for humans (similarities in anatomy in the context of
the disease modeled)
- Transferability of information (similarities in physiology/organ function in the
context of the disease modeled). Is the physiology of the organ(s)/tissue(s) subject
of study conserved in your animal model?
- Genetic conservation of the target gene(s) to model the disease, and of the
mutation in case of inherited diseases. Is there an ortholog of the gene that is key
for the disease that is modelled? Are there paralogs to consider?
- Ease and adaptability to experimental manipulation
- Ethical and ecological implications. Article 9 of Experiments on Animal Act.
- Budget and time (rodents are more expensive compared to fly and zebrafish)
,Lecture 2
Mouse model:
, Around 50% of animals used are mice
Pros
o Lots of offsprings (10-15)
o Closely related to humans
o Genome is fully sequenced
o Many inbred strains characterized
o Genetic mutations well developed
o They are small, have a short generation time and accelerated lifespan
Mice have a different embryo development than humans. In their blastocysts we
can induce mutations.
Anatomy and physiology: comparable to humans
Intestine: really similar structure with comparable digestion process
Microbiome: different bacteria but quite some same ones. It’s used to identify
diseases.
Kidney: identical structure, we have a bit less nephrons. Identical transporters that
can be mimicked fully development of diuretics. But also differences
Vesicles in urine: they have a lot of proteins whose identity tells us something
about the kidney function
Brain: very conserved regions
Methods to model mice:
o Injection (easy, stress)
o Oral gavage (accurate, stress)
o Osmotic pumps (subdermal, continuous flow of drug)
o Food -water (easy, less accurate)
Genetic model: TRPV5 KO
CRISPR/Cas. Plasmid: Advantage of
creating a tissue specific modification. Cas9
is only expressed in the tissue of interest
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