Disease modelling/ drug screening Flashcards
What can cause a healthy state to turn into a diseased state?
1) Infection agents
2) Genetics
3) Doctors
4) Physical damage (raditation, chemicals)
What would need to happen to reverse damage? (drugs)
- Target for the drug to act upon
- The drug has to be discovered
- Drug must be turned into a useable drug and tested on people
What is the process of drug discovery?
1) Target identificaiton
2) Lead selection
3) Lead optimization
4) Pre-clinical development
5) Clinical trail phase 1
6) Clinical trail phase 2 + 3
What does the drug discovery process depend upon?
- Having a target
- Knowing the mechanism (biological processes underlying pathologies)
How can PSCs be used in drug discovery?
- Try to model disease in a dish
- Discover targets
- Test drugs to see if alter the disease phenotype
Why use hPSC to model human disease instead of animal models? (mouse)
Many differences between mice and humans:
1) Developmental biology
- Gastrulation
- Organogenesis
2) Physiological differences
- Heart rate
- Heart size
3) Physical differences
4) Genetic differences
How are genetics different between mice and humans?
- Some mutations in mice are fatal but in humans only cause a disease
- 20% human genes have no orthalogs in mice
What are othlogs?
Genes descended from the same ancestral sequence separated by aspeciationeven
What are the issue of using human cell lines?
- Cells do not grow optimally in medium
- Cell types tend to transform into cancer like cells
- Must change cells, not natural (not in vivo)
- Cells change to enable them to grow in lab environment
What are the 3 advantages of hPSC over conventional cell lines?
1) Normal, primary cell line
2) Grow indefinitely
3) Differentiate into any cellular fate
What is a ‘cell line’?
A cell culture developed from a single cell and therefore consisting of cells with a uniform genetic make-up.
What are the strategies for generating disease models?
1) Gene editing (CRISPR/Cas9) to add mutations
2) Induced pluripotency
What are the 6 criteria for feasibility of modelling a diseasse in vitro and why?
1) Inheritance
- Inherited in one gene is easier
2) Penetrance
- High penetrance is easier
3) Age of onset
- Embryonic is easier
4) Mouse model
- Less likely to do work in diseases with a good mouse model
5) Phenotype
- Easier if the phenotype shows in a cell by cell basis (not pattern formation)
6) Tissue
- Easier if differentiation is easy (make cell type interested in)
What is penetrance?
The proportion of individuals with a specific genotype who express a particular phenotype
What are the 3 ways that phenotypes can be measured?
1) High-throughput screening
2) High-content screening
3) Physiological arrays
