week 2 Flashcards
What is the current drug discovery process?
arduous and costly
What does majority of drug candidate entering clinical trial fail to make?
to the marketplace
What does microengineering and microfluidics provide?
- microeenginering provide precise control over cellular microenvironment
- Microfluidics provide ability to perfuse the constructs on a chip and to connect individual sections with each other
What does the organ-on-a-chip platform be utilized for?
Developing disease model as well as conducting for drug testing studies
Why is there such a low success rate ?
Inability to predict the toxicity and efficacy of drugs before expensive human clinical trials
What does microfabrication and microfluidic technologies create?
small structures for a variety of applications in biotechnology
In drug discovery, what can micro-scale platform allow?
precise delivery of fluids with reduced reagent volumes and can be utilised for high-throughput screening
What can Microengineering technologised be used for?
Fabricating tissue-like structures that mimic the natural complexity of tissues
What may these microscale tissue platform be useful in?
Recreating the intricacies of the in-vivo environment with microscale precision and provide mechanical chemical or electrical cues representative of living environment
What can microscale perfusion bioreactors be generated for
Manipulation of biological materials such as proteins, cells or tissues
What can be used to stimulate signals from brain slices?
the fabrication of
metal electrodes on ultra thin stretchable substrates
what is being developed to
monitor tissue viability and functionality in real-time
on-chip sensors
What can ‘organs-on-a-chip’ provide?
opportunities to probe the
cellular behavior against a plethora of stimuli
What can organ-on-chip create?
- disease models
2. perfused to create dynamic culture environments
What did Aubin et al study?
three-dimensional functionality of cardiac tissue using microscale hydrogels
What did Aubin et el do?
- cardiomyctes were encapsulated inside hydrogels with different micropatterns and align and form fiber-like structures
What did the results of Aubin et al study indicate?
Microscale scaffolds could be engineered to mimic the size and shape of individual cardiac fibers in vivo
What did Giridharan et al culture?
embryonic cardiac cells inside a microscale cylindrical bioreactor and exposed them to pulsatile flow and varying strains to mimic cardiac cycle in left heart ventricle
What can devices like merging, electrical, chemical and mechanical impulses with a tissue culture reactor be utilized for?
Studies of human stem-cell derived cardiac cells
- predict toxicity of drugs and environmental agents on the human heart
- enable development of more efficient treatment for common diseases such as arrythmia
- lead to personalized medicine - allow drug testing on patients own cells to maximise success of treatment
Define medical translation
The practice of translating various documents
- training materials
- medical bulletins
- drug data sheets
for health care
What is important in the medical field for translation?
Avoid all errors in comprehension, change or suppression of information
What does not often translate effectively to human conditions?
drug efficacy in experimental disease model
what can overreliance on animal studies lead to?
inappropriate conclusion
How do we translate?
pop into cell (GPCR)
talk to evoke a response in cell
messengers may be different to therapeutic target
important to have allosteric mediators to help
What should we consider when doing translation?
- native tissue
- intact neurocircuitry
- species-specific paths/receptors
- therapeutic relevance
- access to disease
Why is host cell coupling mis-leading?
popping loads of receptors into the cell so that an agonist starts to look like an antagonist
What happens as you pop GPCR?
- couples
- secondary messengers
- amplify a response when you start measuring
What is important for drug discovery and for basic biology?
Accurate measurements of affinity and efficacy
what underpins analyses of ligand/receptor interaction in both SAR and mutagenesis analysis
The receptor structure and function
What remains largely unknown?
The molecular basis for morphological, physiological, biochemical and behavioural variation in laboratory mice
What enabled our ability to relate sequence to function?
decoding the complete genome of one strain C57BL/6J (the mouse reference genome)
What accelerated the discovery of mouse sequence diversity?
Creating a complete set of null alleles for all genes
Genome sequence of 17 inbred strains of laboratory mice
Identify almost ten times more variants than previously known
What was used to explore phylogenetic history of laboratory mouse
genome sequence of inbred strains
- examine functional consequence of allele-specific variation on transcript abundance
What does 12% of transcripts show?
Significant tissue-specific expression bias
What was the total count in 17 strains?
56.6M unique sites
What are other types of sequence polymorphism that have previously been difficult to assess on a genome- wide scale?
Indels at 8.8M unqiue sites and 0.28M structural variants
How often are mouse models proven to be relevant to human disease?
- Humans have a different receptor identification
- It is not a simple cell - intact neurocircuitry
- Mice and humans have evolved in and became adapted to different environment
- Mice often respond to experimental intervention in ways that differ strikingly from humans
- mouse strains have phenotypes that differ from human counterparts
A phase III trial
90% of total drug development cost (>1 billon)
What is the GI hormone motilin?
A substance released from the duodenum to increase gastric emptying
In human, where is motilin released from?
Fasting and after eating
